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Sheng F, Li M, Yu JM, Yang SY, Zou L, Yang GJ, Zhang LL. IL-33/ST2 axis in diverse diseases: regulatory mechanisms and therapeutic potential. Front Immunol 2025; 16:1533335. [PMID: 39925809 PMCID: PMC11802536 DOI: 10.3389/fimmu.2025.1533335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 01/02/2025] [Indexed: 02/11/2025] Open
Abstract
Interleukin-33 (IL-33) is a nuclear factor and member of the IL-1 cytokine family. IL-33 is mainly expressed by epithelial and endothelial cells and exerts its function through interaction with various immune cells, and binding to its receptor can form the IL-33/Suppression of tumorigenicity 2 (ST2) signaling pathway. While most cytokines are actively synthesized within cells, IL-33 is produced passively in response to tissue damage or cell necrosis, indicating its role as a signaling molecule following cellular infection, stress, or trauma. IL-33/ST2 signaling pathway has been proved to play diverse role in the pathological process of central nervous system disorders, cancer, fibrosis, autoimmune diseases, etc. Although research on the IL-33/ST2 signaling pathway has deepened recently, relevant treatment strategies have been proposed, and even targeted drugs are in the preclinical stage; further research on the effect of the IL-33/ST2 signaling pathway in different diseases is still necessary, to provide a clearer understanding of the different roles of IL-33/ST2 in disease progression and to develop new drugs and treatment strategies. Because IL-33/ST2 plays an important role in the occurrence and progression of diseases, the study of therapeutic drugs targeting this pathway is also necessary. This review focused on recent studies on the positive or negative role of IL-33/ST2 in different diseases, as well as the current related drugs targeting IL-33/ST2 in the preclinical and clinical stage. The mechanism of IL-33/ST2 in different diseases and its mediating effect on different immune cells have been summarized, as well as the antibody drugs targeting IL-33 or ST2, natural compounds with a mediating effect, and small molecule substances targeting relative pathway. We aim to provide new ideas and treatment strategies for IL-33/ST2-related drugs to treat different diseases.
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Affiliation(s)
- Feiya Sheng
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
| | - Mi Li
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Jia-Mei Yu
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Si-Yu Yang
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro−Products, Ningbo University, Ningbo, China
| | - Le-Le Zhang
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, Macao SAR, China
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Boziki M, Theotokis P, Kesidou E, Nella M, Bakirtzis C, Karafoulidou E, Tzitiridou-Chatzopoulou M, Doulberis M, Kazakos E, Deretzi G, Grigoriadis N, Kountouras J. Impact of Mast Cell Activation on Neurodegeneration: A Potential Role for Gut-Brain Axis and Helicobacter pylori Infection. Neurol Int 2024; 16:1750-1778. [PMID: 39728753 DOI: 10.3390/neurolint16060127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/08/2024] [Accepted: 12/03/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND The innate immune response aims to prevent pathogens from entering the organism and/or to facilitate pathogen clearance. Innate immune cells, such as macrophages, mast cells (MCs), natural killer cells and neutrophils, bear pattern recognition receptors and are thus able to recognize common molecular patterns, such as pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), the later occurring in the context of neuroinflammation. An inflammatory component in the pathology of otherwise "primary cerebrovascular and neurodegenerative" disease has recently been recognized and targeted as a means of therapeutic intervention. Activated MCs are multifunctional effector cells generated from hematopoietic stem cells that, together with dendritic cells, represent first-line immune defense mechanisms against pathogens and/or tissue destruction. METHODS This review aims to summarize evidence of MC implication in the pathogenesis of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. RESULTS In view of recent evidence that the gut-brain axis may be implicated in the pathogenesis of neurodegenerative diseases and the characterization of the neuroinflammatory component in the pathology of these diseases, this review also focuses on MCs as potential mediators in the gut-brain axis bi-directional communication and the possible role of Helicobacter pylori, a gastric pathogen known to alter the gut-brain axis homeostasis towards local and systemic pro-inflammatory responses. CONCLUSION As MCs and Helicobacter pylori infection may offer targets of intervention with potential therapeutic implications for neurodegenerative disease, more clinical and translational evidence is needed to elucidate this field.
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Affiliation(s)
- Marina Boziki
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Paschalis Theotokis
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Evangelia Kesidou
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Maria Nella
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Christos Bakirtzis
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Eleni Karafoulidou
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Maria Tzitiridou-Chatzopoulou
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
- Midwifery Department, School of Healthcare Sciences, University of West Macedonia, Koila, 50100 Kozani, Greece
| | - Michael Doulberis
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
- Gastroklinik, Private Gastroenterological Practice, 8810 Horgen, Switzerland
- Division of Gastroenterology and Hepatology, Medical University Department, 5001 Aarau, Switzerland
| | - Evangelos Kazakos
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Georgia Deretzi
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
- Department of Neurology, Papageorgiou General Hospital, 54629 Thessaloniki, Greece
| | - Nikolaos Grigoriadis
- Laboratory of Experimental Neurology and Neuroimmunology, the Multiple Sclerosis Center, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Jannis Kountouras
- Second Medical Clinic, School of Medicine, Ippokration Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
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Liang Y, Zhong G, Li Y, Ren M, Wang A, Ying M, Liu C, Guo Y, Zhang D. Comprehensive Analysis and Experimental Validation of the Parkinson's Disease Lysosomal Gene ACP2 and Pan-cancer. Biochem Genet 2024; 62:4408-4431. [PMID: 38310198 DOI: 10.1007/s10528-023-10652-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 12/27/2023] [Indexed: 02/05/2024]
Abstract
The pivotal role of lysosomal function in preserving neuronal homeostasis is recognized, with its dysfunction being implicated in neurodegenerative processes, notably in Parkinson's disease (PD). Yet, the molecular underpinnings of lysosome-related genes (LRGs) in the context of PD remain partially elucidated. We collected RNA-seq data from the brain substantia nigra of 30 PD patients and 20 normal subjects from the GEO database. We obtained molecular classification clusters from the screened lysosomal expression patterns. The lysosome-related diagnostic model of Parkinson's disease was constructed by XGBoost and Random Forest. And we validated the expression patterns of signature LRGs in the diagnostic model by constructing a PD rat model. Finally, the linkage between PD and cancer through signature genes was explored. The expression patterns of the 33 LRGs screened can be divided into two groups of PD samples, enabling exploration of the variance in biological processes and immune elements. Cluster A had a higher disease severity. Subsequently, critical genes were sieved through the application of machine learning methodologies culminating in the identification of two intersecting feature genes (ACP2 and LRP2). A PD risk prediction model was constructed grounded on these signature genes. The model's validity was assessed through nomogram evaluation, which demonstrated robust confidence validity. Then we analyzed the correlation analysis, immune in-filtration, biological function, and rat expression validation of the two genes with common pathogenic genes in Parkinson's disease, indicating that these two genes play an important role in the pathogenesis of PD. We then selected ACP2, which had a significant immune infiltration correlation, as the entry gene for the pan-cancer analysis. The pan-cancer analysis revealed that ACP2 has profound associations with prognostic indicators, immune infiltration, and tumor-related regulatory processes across various neoplasms, suggesting its potential as a therapeutic target in a range of human diseases, including PD and cancers. Our study comprehensively analyzed the molecular grouping of LRGs expression patterns in Parkinson's disease, and the disease progression was more severe in cluster A. And the PD diagnosis model related to LRGs is constructed. Finally, ACP2 is a potential target for the relationship between Parkinson's disease and tumor.
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Affiliation(s)
- Yu Liang
- School of Clinical Medicine, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233000, China
| | - Guangshang Zhong
- School of Clinical Medicine, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233000, China
| | - Yangyang Li
- School of Life Sciences, Bengbu Medical College, Bengbu, 233000, China
| | - Mingxin Ren
- School of Clinical Medicine, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233000, China
| | - Ao Wang
- School of Clinical Medicine, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233000, China
| | - Mengjiao Ying
- School of Life Sciences, Bengbu Medical College, Bengbu, 233000, China
| | - Changqing Liu
- School of Life Sciences, Bengbu Medical College, Bengbu, 233000, China.
| | - Yu Guo
- School of Clinical Medicine, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233000, China.
- School of Life Sciences, Bengbu Medical College, Bengbu, 233000, China.
| | - Ding Zhang
- School of Life Sciences, Bengbu Medical College, Bengbu, 233000, China.
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Koss KM, Son T, Li C, Hao Y, Cao J, Churchward MA, Zhang ZJ, Wertheim JA, Derda R, Todd KG. Toward discovering a novel family of peptides targeting neuroinflammatory states of brain microglia and astrocytes. J Neurochem 2024; 168:3386-3414. [PMID: 37171455 PMCID: PMC10640667 DOI: 10.1111/jnc.15840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/13/2023]
Abstract
Microglia are immune-derived cells critical to the development and healthy function of the brain and spinal cord, yet are implicated in the active pathology of many neuropsychiatric disorders. A range of functional phenotypes associated with the healthy brain or disease states has been suggested from in vivo work and were modeled in vitro as surveying, reactive, and primed sub-types of primary rat microglia and mixed microglia/astrocytes. It was hypothesized that the biomolecular profile of these cells undergoes a phenotypical change as well, and these functional phenotypes were explored for potential novel peptide binders using a custom 7 amino acid-presenting M13 phage library (SX7) to identify unique peptides that bind differentially to these respective cell types. Surveying glia were untreated, reactive were induced with a lipopolysaccharide treatment, recovery was modeled with a potent anti-inflammatory treatment dexamethasone, and priming was determined by subsequently challenging the cells with interferon gamma. Microglial function was profiled by determining the secretion of cytokines and nitric oxide, and expression of inducible nitric oxide synthase. After incubation with the SX7 phage library, populations of SX7-positive microglia and/or astrocytes were collected using fluorescence-activated cell sorting, SX7 phage was amplified in Escherichia coli culture, and phage DNA was sequenced via next-generation sequencing. Binding validation was done with synthesized peptides via in-cell westerns. Fifty-eight unique peptides were discovered, and their potential functions were assessed using a basic local alignment search tool. Peptides potentially originated from proteins ranging in function from a variety of supportive glial roles, including synapse support and pruning, to inflammatory incitement including cytokine and interleukin activation, and potential regulation in neurodegenerative and neuropsychiatric disorders.
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Affiliation(s)
- K M Koss
- Comprehensive Transplant Center and Department of Surgery, Feinberg School of Medicine, Northwestern University, Illinois, Chicago, USA
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Alberta, Edmonton, Canada
- Department of Surgery, University of Arizona College of Medicine, Arizona, Tucson, USA
| | - T Son
- Comprehensive Transplant Center and Department of Surgery, Feinberg School of Medicine, Northwestern University, Illinois, Chicago, USA
| | - C Li
- Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr NW, Edmonton, AB T6G 2G2, Canada
| | - Y Hao
- Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr NW, Edmonton, AB T6G 2G2, Canada
| | - J Cao
- Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr NW, Edmonton, AB T6G 2G2, Canada
- 48Hour Discovery Inc, 11421 Saskatchewan Dr NW, Edmonton, AB T6G 2M9, Canada
| | - M A Churchward
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Alberta, Edmonton, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Alberta, Edmonton, Canada
- Department of Biology and Environmental Sciences, Concordia University of Edmonton, Alberta, Edmonton, Canada
| | - Z J Zhang
- Comprehensive Transplant Center and Department of Surgery, Feinberg School of Medicine, Northwestern University, Illinois, Chicago, USA
| | - J A Wertheim
- Comprehensive Transplant Center and Department of Surgery, Feinberg School of Medicine, Northwestern University, Illinois, Chicago, USA
- Department of Surgery, University of Arizona College of Medicine, Arizona, Tucson, USA
| | - R Derda
- Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr NW, Edmonton, AB T6G 2G2, Canada
- 48Hour Discovery Inc, 11421 Saskatchewan Dr NW, Edmonton, AB T6G 2M9, Canada
| | - K G Todd
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Alberta, Edmonton, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Alberta, Edmonton, Canada
- Department of Biomedical Engineering, University of Alberta, Alberta, Edmonton, Canada
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Netzahualcoyotzi C, Santillán-Cigales JJ, Adalid-Peralta LV, Velasco I. Infiltration of immune cells to the brain and its relation to the pathogenesis of Alzheimer's and Parkinson's diseases. J Neurochem 2024; 168:2316-2334. [PMID: 38549444 DOI: 10.1111/jnc.16106] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 02/22/2024] [Accepted: 03/13/2024] [Indexed: 10/04/2024]
Abstract
The neurovascular unit, composed of vascular endothelium, vascular smooth muscle, extracellular matrix components, pericytes, astrocytes, microglia, and neurons, allows the highly regulated exchange of molecules and the limited trafficking of cells to the brain through coordinated signaling activity. The passage of peripheral immune cells to the brain parenchyma is observed when there is clear damage to the barriers of this neurovascular unit, as occurs in traumatic brain injury. The possibility of leukocyte infiltration to the brain in neurodegenerative conditions has been proposed. In this review, we focus on describing the evidence for peripheral immune cell infiltration to the brain in the two most frequent neurodegenerative diseases: Alzheimer's and Parkinson's diseases. In particular, we address the mechanisms that promote the passage of these cells into the brain under such pathological conditions. We also discuss the relevance of the resulting cellular interactions, which provide evidence that the presence of peripheral immune cells in the brain is a key point in these neurodegenerative diseases.
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Affiliation(s)
- Citlalli Netzahualcoyotzi
- Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - Juan Jair Santillán-Cigales
- Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Laura Virginia Adalid-Peralta
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
| | - Iván Velasco
- Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico
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Huang X, Lan Z, Hu Z. Role and mechanisms of mast cells in brain disorders. Front Immunol 2024; 15:1445867. [PMID: 39253085 PMCID: PMC11381262 DOI: 10.3389/fimmu.2024.1445867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 08/12/2024] [Indexed: 09/11/2024] Open
Abstract
Mast cells serve as crucial effector cells within the innate immune system and are predominantly localized in the skin, airways, gastrointestinal tract, urinary and reproductive tracts, as well as in the brain. Under physiological conditions, brain-resident mast cells secrete a diverse array of neuro-regulatory mediators to actively participate in neuroprotection. Meanwhile, as the primary source of molecules causing brain inflammation, mast cells also function as the "first responders" in brain injury. They interact with neuroglial cells and neurons to facilitate the release of numerous inflammatory mediators, proteases, and reactive oxygen species. This process initiates and amplifies immune-inflammatory responses in the brain, thereby contributing to the regulation of neuroinflammation and blood-brain barrier permeability. This article provides a comprehensive overview of the potential mechanisms through which mast cells in the brain may modulate neuroprotection and their pathological implications in various neurological disorders. It is our contention that the inhibition of mast cell activation in brain disorders could represent a novel avenue for therapeutic breakthroughs.
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Affiliation(s)
- Xuanyu Huang
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ziwei Lan
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiping Hu
- Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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Hernández-Aguilar I, Vizuet-de-Rueda JC, Galván-Morales MÁ, Montero-Vargas JM, Teran LM. Rapid generation of an RBL cellular model to study proteins that cause allergenic reactions in vitro. Immunol Res 2024; 72:874-879. [PMID: 38334936 PMCID: PMC11347464 DOI: 10.1007/s12026-024-09461-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 01/26/2024] [Indexed: 02/10/2024]
Abstract
Allergic diseases affect nearly 30% of people worldwide. There is a wide range of allergen sources, such as animal dander, food, venom, dust mites, and pollen. The skin prick test is the predominant technique used to identify allergenic sensitivity in vivo; the main problem is that it can be imprecise as many of the allergen extracts are made of mixtures of allergic and nonallergic components, making it difficult to identify the disease-eliciting allergen. An alternative to solve this problem is employing cellular models in vitro that may allow allergen identification, allergy diagnosis, and testing of novel potential compounds that can be used in immunotherapeutics. For example, rat basophilic leukemia (RBL) cells are a well-suited model for studying allergies. Unfortunately, cells generated from RBL cells are not commercially available. Therefore, we developed an RBL model with a degranulation gene reporter capable of recognizing human IgE involved in allergenic sensitivity using commercial plasmids. Employing this model, we successfully evaluated the capacity of union between IgE from allergic patients to allergenic proteins from Oleaceae tree pollen. This RBL cell model can be used as a diagnostic method for sensitivity to any allergens from different sources in vitro.
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Affiliation(s)
- Israel Hernández-Aguilar
- Ciencias Básicas en Biología, Instituto Tecnológico del Valle de Oaxaca, Ex-Hda. de Nazareno, Santa Cruz Xoxocotlán, 10587, Oaxaca, México
| | - Juan Carlos Vizuet-de-Rueda
- Depto. de Inmunogenética y Alergia, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calz. de Tlalpan 4502, Tlapan, 14080, Ciudad de Mexico, México
| | - Miguel Ángel Galván-Morales
- Depto. de Inmunogenética y Alergia, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calz. de Tlalpan 4502, Tlapan, 14080, Ciudad de Mexico, México
| | - Josaphat Miguel Montero-Vargas
- Depto. de Inmunogenética y Alergia, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calz. de Tlalpan 4502, Tlapan, 14080, Ciudad de Mexico, México
| | - Luis M Teran
- Depto. de Inmunogenética y Alergia, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calz. de Tlalpan 4502, Tlapan, 14080, Ciudad de Mexico, México.
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Xie S, Peng P, Dong X, Yuan J, Liang J. Novel gene signatures predicting and immune infiltration analysis in Parkinson's disease: based on combining random forest with artificial neural network. Neurol Sci 2024; 45:2681-2696. [PMID: 38265536 DOI: 10.1007/s10072-023-07299-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 12/29/2023] [Indexed: 01/25/2024]
Abstract
BACKGROUND Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative disorder globally, and its incidence is rapidly rising. The diagnosis of PD relies on clinical characteristics. Although current treatments aim to alleviate symptoms, they do not effectively halt the disease's progression. Early detection and intervention hold immense importance. This study aimed to establish a new PD diagnostic model. METHODS Data from a public database were adopted for the construction and validation of a PD diagnostic model with random forest and artificial neural network models. The CIBERSORT platform was applied for the evaluation of immune cell infiltration in PD. Quantitative real-time PCR was performed to verify the accuracy and reliability of the bioinformatics analysis results. RESULTS Leveraging existing gene expression data from the Gene Expression Omnibus (GEO) database, we sifted through differentially expressed genes (DEGs) in PD and identified 30 crucial genes through a random forest classifier. Furthermore, we successfully designed a novel PD diagnostic model using an artificial neural network and verified its diagnostic efficacy using publicly available datasets. Our research also suggests that mast cells may play a significant role in the onset and progression of PD. CONCLUSION This work developed a new PD diagnostic model with machine learning techniques and suggested the immune cells as a potential target for PD therapy.
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Affiliation(s)
- Shucai Xie
- Department of Critical Care Medicine, National Clinical Research Center for Genetic Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Pei Peng
- Department of Medicine Oncology, Changde Hospital, Xiangya School of Medicine, Central South University (The first people's hospital of Changde city), Changde, China
| | - Xingcheng Dong
- Department of Orthopedics, Changde Hospital, Xiangya School of Medicine, Central South University (The first people's hospital of Changde city), Changde, China
| | - Junxing Yuan
- Department of Neurology, Changde Hospital, Xiangya School of Medicine, Central South University (The first people's hospital of Changde city), No. 818 Renmin Road, Changde, 415000, Hunan, China
| | - Ji Liang
- Department of Neurology, Changde Hospital, Xiangya School of Medicine, Central South University (The first people's hospital of Changde city), No. 818 Renmin Road, Changde, 415000, Hunan, China.
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9
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Theoharides TC, Twahir A, Kempuraj D. Mast cells in the autonomic nervous system and potential role in disorders with dysautonomia and neuroinflammation. Ann Allergy Asthma Immunol 2024; 132:440-454. [PMID: 37951572 DOI: 10.1016/j.anai.2023.10.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/16/2023] [Accepted: 10/06/2023] [Indexed: 11/14/2023]
Abstract
Mast cells (MC) are ubiquitous in the body, and they are critical for not only in allergic diseases but also in immunity and inflammation, including having potential involvement in the pathophysiology of dysautonomias and neuroinflammatory disorders. MC are located perivascularly close to nerve endings and sites such as the carotid bodies, heart, hypothalamus, the pineal gland, and the adrenal gland that would allow them not only to regulate but also to be affected by the autonomic nervous system (ANS). MC are stimulated not only by allergens but also many other triggers including some from the ANS that can affect MC release of neurosensitizing, proinflammatory, and vasoactive mediators. Hence, MC may be able to regulate homeostatic functions that seem to be dysfunctional in many conditions, such as postural orthostatic tachycardia syndrome, autism spectrum disorder, myalgic encephalomyelitis/chronic fatigue syndrome, and Long-COVID syndrome. The evidence indicates that there is a possible association between these conditions and diseases associated with MC activation. There is no effective treatment for any form of these conditions other than minimizing symptoms. Given the many ways MC could be activated and the numerous mediators released, it would be important to develop ways to inhibit stimulation of MC and the release of ANS-relevant mediators.
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Affiliation(s)
- Theoharis C Theoharides
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, Florida; Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts.
| | - Assma Twahir
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, Florida
| | - Duraisamy Kempuraj
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, Florida
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10
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Cohen J, Mathew A, Dourvetakis KD, Sanchez-Guerrero E, Pangeni RP, Gurusamy N, Aenlle KK, Ravindran G, Twahir A, Isler D, Sosa-Garcia SR, Llizo A, Bested AC, Theoharides TC, Klimas NG, Kempuraj D. Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders. Cells 2024; 13:511. [PMID: 38534355 PMCID: PMC10969521 DOI: 10.3390/cells13060511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 03/03/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Neuroinflammatory and neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.
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Affiliation(s)
- Jessica Cohen
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Annette Mathew
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Kirk D Dourvetakis
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Estella Sanchez-Guerrero
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Rajendra P Pangeni
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Narasimman Gurusamy
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Kristina K Aenlle
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
- Miami VA Geriatric Research Education and Clinical Center (GRECC), Miami Veterans Affairs Healthcare System, Miami, FL 33125, USA
| | - Geeta Ravindran
- Cell Therapy Institute, Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Assma Twahir
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Dylan Isler
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Sara Rukmini Sosa-Garcia
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Axel Llizo
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Alison C Bested
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
| | - Theoharis C Theoharides
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
- Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Nancy G Klimas
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
- Miami VA Geriatric Research Education and Clinical Center (GRECC), Miami Veterans Affairs Healthcare System, Miami, FL 33125, USA
| | - Duraisamy Kempuraj
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL 33328, USA
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Wang R, Zeng J, Chen L, Sun L, Wang Y, Xu J, He X. Diterpenoid WT-29 isolated from Wedelia exerted anti-inflammatory and anti-allergic activities. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117265. [PMID: 37783409 DOI: 10.1016/j.jep.2023.117265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/23/2023] [Accepted: 09/29/2023] [Indexed: 10/04/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Wedelia (Sphagneticola trilobata) is a traditional anti-inflammatory herb native to tropical America. It is commonly used to treat some inflammatory related diseases clinically, such as pertussis, pharyngitis, etc. However, its specific anti-inflammatory mechanism is still unclear. AIM OF THE STUDY WT-29 (3α-angeloyloxy-9β-hydroxyent-kaura-16-en-19-oic acid) is a main bioactive diterpenoid isolated and purified from Wedelia. This study aims to explore the potential anti-inflammatory and anti-allergic properties of WT-29 on RAW264.7 cells stimulated with LPS and P815 cells induced by C48/80, as well as investigating their underlying molecular mechanisms. METHODS The anti-inflammatory mechanism of WT-29 was analyzed and predicted using network pharmacology, and then verified through experiments. The Griess reagent assay was employed to evaluate the impact of WT-29 on the generation of nitric oxide (NO) in RAW264.7 cells induced by LPS, the expression of various inflammatory cytokines and the release of histamine in cells were measured through qRT-PCR and ELISA techniques. The impact of WT-29 on the translocation of the NF-κB p65 protein to the nucleus was assessed through immunofluorescence staining. Western blot technique was utilized to investigate protein expression in inflammation, allergy, and autophagy pathways. RESULTS The study found that WT-29 can reduce the secretion of inflammatory factors (NO, iNOS, COX-2, IL-6, IL-1β and TNF-α), inhibit NF-κB activation and MAPK family phosphorylation, and induce autophagy in RAW264.7 cells stimulated with LPS. In addition, it demonstrated that WT-29 could inhibit histamine release and degranulation, as well as inhibit the MAPK family in C48/80-induced P815 cells. CONCLUSION WT-29 isolated from Wedelia exerts anti-inflammatory and anti-allergic effects mainly through NF-κB, Nrf2/Keap-1, MAPK pathways and regulating of autophagy, suggesting that it might be a potential anti-inflammatory and anti-allergic agent and could be used as medicine or health benefit product.
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Affiliation(s)
- Ru Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, 510006, China.
| | - Jia Zeng
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Lu Chen
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, 510006, China.
| | - Lianlian Sun
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, 510006, China.
| | - Yihai Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, 510006, China.
| | - Jingwen Xu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, 510006, China.
| | - Xiangjiu He
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, 510006, China.
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12
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Huang HT, Tzeng SF. Interleukin-33 has the protective effect on oligodendrocytes against impairment induced by cuprizone intoxication. Neurochem Int 2024; 172:105645. [PMID: 38016520 DOI: 10.1016/j.neuint.2023.105645] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 11/09/2023] [Accepted: 11/21/2023] [Indexed: 11/30/2023]
Abstract
Our prior investigations have demonstrated the pivotal role of IL-33 in facilitating the maturation of oligodendrocytes (OLs), prompting our interest in exploring its potential therapeutic effects. In this study, our focus was directed towards deciphering the functions of interleukin-33 (IL-33) in established demyelinating mouse model induced by the feeding of cuprizone (CPZ)-containing diet. We observed the reduction in corpus callosal adenomatous polyposis coli (APC)+ OLs with IL-33 expression in mice subjected to CPZ feeding for durations of 6 and 8 weeks. In parallel, the levels of IL-33 in the corpus callosum declined after CPZ-containing diet. Furthermore, we conducted experiments utilizing primary oligodendrocyte precursor cells (OPCs) and mature OLs, which were exposed to CPZ. A decrease in the expression of myelin basic protein (MBP) was evident in the cultures of mature OLs after treatment with CPZ. Additionally, both IL-33 mRNA and protein levels exhibited downregulation. To counteract the diminished IL-33 levels induced by CPZ, we employed a lentiviral vector to overexpress IL-33 in OLs. Intriguingly, the overexpression of IL-33 (IL33OE) in OLs resulted in a more distinct membranous morphology following CPZ treatment when compared to that observed in OL Mock cultures. Moreover, MBP protein levels in the presence of CPZ were higher in IL33OE OLs than that detected in OL Mock cultures. These findings collectively indicate that IL-33 possesses the capability to mitigate CPZ-induced damage and bolster OL homeostasis. In summary, our study underscores the importance of IL-33 in the context of demyelinating diseases, shedding light on its potential therapeutic implications for fostering remyelination and preserving OL function.
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Affiliation(s)
- Hui-Ting Huang
- Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan
| | - Shun-Fen Tzeng
- Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan.
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Ai J, Weng Y, Jiang L, Liu C, Liu H, Chen H. Dexamethasone Suppresses IL-33-exacerbated Malignant Phenotype of U87MG Glioblastoma Cells via NF-κB and MAPK Signaling Pathways. Anticancer Agents Med Chem 2024; 24:389-397. [PMID: 38192141 DOI: 10.2174/0118715206281991231222073858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/07/2023] [Accepted: 12/14/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND Interleukin (IL)-33 is highly expressed in glioblastoma (GBM) and promotes tumor progression. Targeting IL-33 may be an effective strategy for the treatment of GBM. Dexamethasone (DEX) is a controversial drug routinely used clinically in GBM therapy. Whether DEX has an effect on IL-33 is unknown. This study aimed to investigate the effect of DEX on IL-33 and the molecular mechanisms involved. METHODS U87MG cells were induced by tumor necrosis factor (TNF)-α to express IL-33 and then treated with DEX. The mRNA levels of IL-33, NF-κB p65, ERK1/2, and p38 were determined by real-time quantitative PCR. The expression of IL-33, IkBα (a specific inhibitor of NF-κB) and MKP-1 (a negative regulator of MAPK), as well as the phosphorylation of NF-κB, ERK1/2 and p38 MAPK, were detected by Western blotting. The secretion of IL-33 was measured by ELISA. The proliferation, migration and invasion of U87MG cells were detected by CCK8 and transwell assays, respectively. RESULTS DEX significantly reduced TNF-α-induced production of IL-33 in U87MG cells, which was dependent on inhibiting the activation of the NF-κB, ERK1/2 and p38 MAPK signaling pathways, and was accompanied by the increased expression of IkBα but not MKP-1. Furthermore, the proliferation, migration and invasion of U87MG cells exacerbated by IL-33 were suppressed by DEX. CONCLUSION DEX inhibited the production and tumor-promoting function of IL-33. Whether DEX can benefit GBM patients remains controversial. Our results suggest that GBM patients with high IL-33 expression may benefit from DEX treatment and deserve further investigation.
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Affiliation(s)
- Jie Ai
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, PR China
- College of Pharmacy, Guilin Medical University, Guilin, 541199, PR China
| | - Yinhua Weng
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, PR China
| | - Liyan Jiang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, PR China
| | - Chao Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, PR China
| | - Hongbo Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, PR China
- Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
| | - Huoying Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, PR China
- Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
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14
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Chen L, Xin G, He Y, Tian Q, Kong X, Fu Y, Wang J, Zhang H, Wang L. Study of molecular patterns associated with ferroptosis in Parkinson's disease and its immune signature. PLoS One 2023; 18:e0295699. [PMID: 38127902 PMCID: PMC10734959 DOI: 10.1371/journal.pone.0295699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 11/27/2023] [Indexed: 12/23/2023] Open
Abstract
Parkinson's disease is the second most common neurodegenerative disease in the world. We downloaded data on Parkinson's disease and Ferroptosis-related genes from the GEO and FerrDb databases. We used WCGAN and Random Forest algorithm to screen out five Parkinson's disease ferroptosis-related hub genes. Two genes were identified for the first time as possibly playing a role in Braak staging progression. Unsupervised clustering analysis based on hub genes yielded ferroptosis isoforms, and immune infiltration analysis indicated that these isoforms are associated with immune cells and may represent different immune patterns. FRHGs scores were obtained to quantify the level of ferroptosis modifications in each individual. In addition, differences in interleukin expression were found between the two ferroptosis subtypes. The biological functions involved in the hub gene are analyzed. The ceRNA regulatory network of hub genes was mapped. The disease classification diagnosis model and risk prediction model were also constructed by applying hub genes based on logistic regression. Multiple external datasets validated the hub gene and classification diagnostic model with some accuracy. This study explored hub genes associated with ferroptosis in Parkinson's disease and their molecular patterns and immune signatures to provide new ideas for finding new targets for intervention and predictive biomarkers.
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Affiliation(s)
- Lixia Chen
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, City Harbin, Province Heilongjiang, China
| | - Guanghao Xin
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, City Harbin, Province Heilongjiang, China
| | - Yijie He
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, City Harbin, Province Heilongjiang, China
| | - Qinghua Tian
- Department of Neurology, The 962 Hospital of the Chinese People’s Liberation Army Joint Logistic Support Force, City Harbin, Province Heilongjiang, China
| | - Xiaotong Kong
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, City Harbin, Province Heilongjiang, China
| | - Yanchi Fu
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, City Harbin, Province Heilongjiang, China
| | - Jianjian Wang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, City Harbin, Province Heilongjiang, China
| | - Huixue Zhang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, City Harbin, Province Heilongjiang, China
| | - Lihua Wang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, City Harbin, Province Heilongjiang, China
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15
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Jia Z, Guo M, Ge X, Chen F, Lei P. IL-33/ST2 Axis: A Potential Therapeutic Target in Neurodegenerative Diseases. Biomolecules 2023; 13:1494. [PMID: 37892176 PMCID: PMC10605306 DOI: 10.3390/biom13101494] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/01/2023] [Accepted: 10/03/2023] [Indexed: 10/29/2023] Open
Abstract
Interleukin 33 (IL-33) belongs to the IL-1 family and is localized in the nucleus. IL-33 is primarily composed of three distinct domains, namely the N-terminal domain responsible for nuclear localization, the intermediate sense protease domain, and the C-terminal cytokine domain. Its specific receptor is the suppression of tumorigenicity 2 (ST2), which is detected in serum-stimulated fibroblasts and oncogenes. While most other cytokines are actively produced in cells, IL-33 is passively produced in response to tissue damage or cell necrosis, thereby suggesting its role as an alarm following cell infection, stress, or trauma. IL-33 plays a crucial role in congenital and acquired immunity, which assists in the response to environmental stress and maintains tissue homeostasis. IL-33/ST2 interaction further produces many pro-inflammatory cytokines. Moreover, IL-33 is crucial for central nervous system (CNS) homeostasis and the pathogenic mechanisms underlying CNS degenerative disorders. The present work summarizes the structure of IL-33, its fundamental activities, and its role in immunoregulation and neurodegenerative diseases. Therefore, this work proposes that IL-33 may play a role in the pathogenic mechanism of diseases and can be used in the development of treatment strategies.
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Affiliation(s)
- Zexi Jia
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; (Z.J.); (X.G.)
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Mengtian Guo
- Department of Internal Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100054, China;
| | - Xintong Ge
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; (Z.J.); (X.G.)
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Fanglian Chen
- Tianjin Neurological Institute, Tianjin 300052, China
| | - Ping Lei
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin 300052, China; (Z.J.); (X.G.)
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
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16
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Lin CCJ, Herisson F, Le H, Jaafar N, Chetal K, Oram MK, Flynn KL, Gavrilles EP, Sadreyev RI, Schiffino FL, Tanzi RE. Mast cell deficiency improves cognition and enhances disease-associated microglia in 5XFAD mice. Cell Rep 2023; 42:113141. [PMID: 37713312 PMCID: PMC10634538 DOI: 10.1016/j.celrep.2023.113141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 06/20/2023] [Accepted: 08/30/2023] [Indexed: 09/17/2023] Open
Abstract
Emerging evidence suggests that peripheral immune cells contribute to Alzheimer's disease (AD) neuropathogenesis. Among these, mast cells are known for their functions in allergic reactions and neuroinflammation; however, little is known about their role in AD. Here, we crossed 5XFAD mice with mast cell-deficient strains and observed the effects on AD-related neuropathology and cognitive impairment. We found that mast cell depletion improved contextual fear conditioning in 5XFAD mice without affecting cued fear conditioning, anxiety-like behavior, or amyloid burden. Furthermore, mast cell depletion led to an upregulation of transcriptomic signatures for putatively protective disease-associated microglia and resulted in reduced markers indicative of reactive astrocytes. We hypothesize a system of bidirectional communication between dural mast cells and the brain, where mast cells respond to signals from the brain environment by expressing immune-regulatory mediators, impacting cognition and glial cell function. These findings highlight mast cells as potential therapeutic targets for AD.
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Affiliation(s)
- Chih-Chung Jerry Lin
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Fanny Herisson
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Hoang Le
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Nader Jaafar
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Kashish Chetal
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Mary K Oram
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Kelly L Flynn
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Evan P Gavrilles
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Ruslan I Sadreyev
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Felipe L Schiffino
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Rudolph E Tanzi
- Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Charlestown, MA 02129, USA.
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17
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Bhuiyan P, Sun Z, Chen Y, Qian Y. Peripheral surgery triggers mast cells activation: Focusing on neuroinflammation. Behav Brain Res 2023; 452:114593. [PMID: 37499912 DOI: 10.1016/j.bbr.2023.114593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/12/2023] [Accepted: 07/20/2023] [Indexed: 07/29/2023]
Abstract
Peripheral surgery can lead to a systemic aseptic inflammatory response comprising several mediators aiming at restoring tissue homeostasis. It induces inflammatory mechanisms through neuroimmune interaction between the periphery and to brain which also plays a critical role in causing cognitive impairments. Accumulating scientific evidence revealed that acute neuroinflammation of the brain triggered by peripheral surgery that causes peripheral inflammation leads to transmitting signals into the brain through immune cells. Mast cells (MCs) play an important role in the acute neuroinflammation induced by peripheral surgical trauma. After peripheral surgery, brain-resident MCs can be rapidly activated followed by releasing histamine, tryptase, and other inflammatory mediators. These mediators then interact with other immune cells in the peripheral and amplify the signal into the brain by disrupting BBB and activating principle innate immune cells of brain including microglia, astrocytes, and vascular endothelial cells, which release abundant inflammatory mediators and in turn accelerate the activation of brain MCs, amplify the cascade effect of neuroinflammatory response. Surgical stress may induce HPA axis activation by releasing corticotropin-releasing hormone (CRH) subsequently influence the activation of brain MCs, thus resulting in impaired synaptic plasticity. Herein, we discuss the better understating of MCs mediated neuroinflammation mechanisms after peripheral surgery and potential therapeutic targets for controlling inflammatory cascades.
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Affiliation(s)
- Piplu Bhuiyan
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China
| | - Zhaochu Sun
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China
| | - Yinan Chen
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
| | - Yanning Qian
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, People's Republic of China.
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18
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Theoharides TC, Kempuraj D. Potential Role of Moesin in Regulating Mast Cell Secretion. Int J Mol Sci 2023; 24:12081. [PMID: 37569454 PMCID: PMC10418457 DOI: 10.3390/ijms241512081] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Mast cells have existed for millions of years in species that never suffer from allergic reactions. Hence, in addition to allergies, mast cells can play a critical role in homeostasis and inflammation via secretion of numerous vasoactive, pro-inflammatory and neuro-sensitizing mediators. Secretion may utilize different modes that involve the cytoskeleton, but our understanding of the molecular mechanisms regulating secretion is still not well understood. The Ezrin/Radixin/Moesin (ERM) family of proteins is involved in linking cell surface-initiated signaling to the actin cytoskeleton. However, how ERMs may regulate secretion from mast cells is still poorly understood. ERMs contain two functional domains connected through a long α-helix region, the N-terminal FERM (band 4.1 protein-ERM) domain and the C-terminal ERM association domain (C-ERMAD). The FERM domain and the C-ERMAD can bind to each other in a head-to-tail manner, leading to a closed/inactive conformation. Typically, phosphorylation on the C-terminus Thr has been associated with the activation of ERMs, including secretion from macrophages and platelets. It has previously been shown that the ability of the so-called mast cell "stabilizer" disodium cromoglycate (cromolyn) to inhibit secretion from rat mast cells closely paralleled the phosphorylation of a 78 kDa protein, which was subsequently shown to be moesin, a member of ERMs. Interestingly, the phosphorylation of moesin during the inhibition of mast cell secretion was on the N-terminal Ser56/74 and Thr66 residues. This phosphorylation pattern could lock moesin in its inactive state and render it inaccessible to binding to the Soluble NSF attachment protein receptors (SNAREs) and synaptosomal-associated proteins (SNAPs) critical for exocytosis. Using confocal microscopic imaging, we showed moesin was found to colocalize with actin and cluster around secretory granules during inhibition of secretion. In conclusion, the phosphorylation pattern and localization of moesin may be important in the regulation of mast cell secretion and could be targeted for the development of effective inhibitors of secretion of allergic and inflammatory mediators from mast cells.
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Affiliation(s)
- Theoharis C. Theoharides
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
- Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Duraisamy Kempuraj
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
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Theoharides TC, Kempuraj D. Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID. Cells 2023; 12:688. [PMID: 36899824 PMCID: PMC10001285 DOI: 10.3390/cells12050688] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/07/2023] [Accepted: 02/16/2023] [Indexed: 02/24/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae of SARS-CoV-2 (PASC), referred to as "Long-COVID," characterized by persistent physical and mental fatigue. However, the exact pathogenetic mechanisms affecting the brain are still not well-understood. There is increasing evidence of neurovascular inflammation in the brain. However, the precise role of the neuroinflammatory response that contributes to the disease severity of COVID-19 and long COVID pathogenesis is not clearly understood. Here, we review the reports that the SARS-CoV-2 spike protein can cause blood-brain barrier (BBB) dysfunction and damage neurons either directly, or via activation of brain mast cells and microglia and the release of various neuroinflammatory molecules. Moreover, we provide recent evidence that the novel flavanol eriodictyol is particularly suited for development as an effective treatment alone or together with oleuropein and sulforaphane (ViralProtek®), all of which have potent anti-viral and anti-inflammatory actions.
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Affiliation(s)
- Theoharis C. Theoharides
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
- Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Duraisamy Kempuraj
- Institute for Neuro-Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
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20
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Tan YJ, Siow I, Saffari SE, Ting SKS, Li Z, Kandiah N, Tan LCS, Tan EK, Ng ASL. Plasma Soluble ST2 Levels Are Higher in Neurodegenerative Disorders and Associated with Poorer Cognition. J Alzheimers Dis 2023; 92:573-580. [PMID: 36776067 DOI: 10.3233/jad-221072] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
BACKGROUND Suppressor of tumorgenicity 2 (ST2) is highly expressed in brain tissue and is a receptor for interleukin 33 (IL-33). ST2 exists in two forms, a transmembrane receptor (ST2L) and a soluble decoy receptor (sST2). IL-33 binds to ST2L, triggering downstream signaling pathways involved in amyloid plaque clearance. Conversely, sST2 binds competitively to IL-33, attenuating its neuroprotective effects. High sST2 levels have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), suggesting that the IL-33/ST2 signaling pathway may be implicated in neurodegenerative diseases. OBJECTIVE To investigate plasma sST2 levels in controls and patients with MCI, AD, frontotemporal dementia (FTD), and Parkinson's disease (PD). METHODS Plasma sST2 levels were measured using ELISA in 397 subjects (91 HC, 46 MCI, 38 AD, 28 FTD, and 194 PD). Cerebrospinal fluid (CSF) levels of sST2 were measured in 22 subjects. Relationship between sST2 and clinical outcomes were analyzed. RESULTS Plasma sST2 levels were increased across all disease groups compared to controls, with highest levels seen in FTD followed by AD and PD. Dementia patients with higher sST2 had lower cross-sectional cognitive scores in Frontal Assessment Battery and Digit Span Backward. At baseline, PD-MCI patients had higher sST2, associated with worse attention. In the longitudinal PD cohort, higher sST2 significantly associated with decline in global cognition and visuospatial domains. Plasma sST2 levels correlated with CSF sST2 levels. CONCLUSION Plasma sST2 is raised across neurodegenerative diseases and is associated with poorer cognition. Higher baseline sST2 is a potential biomarker of disease severity in neurodegeneration.
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Affiliation(s)
- Yi Jayne Tan
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore
| | - Isabel Siow
- Ministry of Health Holdings, Singapore, Singapore
| | - Seyed Ehsan Saffari
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.,Center for Quantitative Medicine, Duke-NUS Medical School, National University of Singapore, Singapore
| | - Simon K S Ting
- Department of Neurology, Singapore General Hospital, Singapore
| | - Zeng Li
- Neural Stem Cell Research Lab, Department of Research, National Neuroscience Institute, Singapore
| | - Nagaendran Kandiah
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore
| | - Louis C S Tan
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore
| | - Eng King Tan
- Center for Quantitative Medicine, Duke-NUS Medical School, National University of Singapore, Singapore.,Neuroscience and Behavioural Disorders Unit, Duke-NUS Medical School, Singapore
| | - Adeline S L Ng
- Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.,Neuroscience and Behavioural Disorders Unit, Duke-NUS Medical School, Singapore
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21
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Xiong Y, Chen J, Li Y. Microglia and astrocytes underlie neuroinflammation and synaptic susceptibility in autism spectrum disorder. Front Neurosci 2023; 17:1125428. [PMID: 37021129 PMCID: PMC10067592 DOI: 10.3389/fnins.2023.1125428] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/03/2023] [Indexed: 04/07/2023] Open
Abstract
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with onset in childhood. The mechanisms underlying ASD are unclear. In recent years, the role of microglia and astrocytes in ASD has received increasing attention. Microglia prune the synapses or respond to injury by sequestrating the injury site and expressing inflammatory cytokines. Astrocytes maintain homeostasis in the brain microenvironment through the uptake of ions and neurotransmitters. However, the molecular link between ASD and microglia and, or astrocytes remains unknown. Previous research has shown the significant role of microglia and astrocytes in ASD, with reports of increased numbers of reactive microglia and astrocytes in postmortem tissues and animal models of ASD. Therefore, an enhanced understanding of the roles of microglia and astrocytes in ASD is essential for developing effective therapies. This review aimed to summarize the functions of microglia and astrocytes and their contributions to ASD.
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22
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Rao X, Hua F, Zhang L, Lin Y, Fang P, Chen S, Ying J, Wang X. Dual roles of interleukin-33 in cognitive function by regulating central nervous system inflammation. J Transl Med 2022; 20:369. [PMID: 35974336 PMCID: PMC9382782 DOI: 10.1186/s12967-022-03570-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 08/04/2022] [Indexed: 12/13/2022] Open
Abstract
With the advent of an aging society, the incidence of dementia is increasing, resulting in a vast burden on society. It is increasingly acknowledged that neuroinflammation is implicated in various neurological diseases with cognitive dysfunction such as Alzheimer’s disease, multiple sclerosis, ischemic stroke, traumatic brain injury, and central nervous system infections. As an important neuroinflammatory factor, interleukin-33 (IL-33) is highly expressed in various tissues and cells in the mammalian brain, where it plays a role in the pathogenesis of a number of central nervous system conditions. Reams of previous studies have shown that IL-33 has both pro- and anti-inflammatory effects, playing dual roles in the progression of diseases linked to cognitive impairment by regulating the activation and polarization of immune cells, apoptosis, and synaptic plasticity. This article will summarize the current findings on the effects IL-33 exerts on cognitive function by regulating neuroinflammation, and attempt to explore possible therapeutic strategies for cognitive disorders based on the adverse and protective mechanisms of IL-33.
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Affiliation(s)
- Xiuqin Rao
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Fuzhou Hua
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Lieliang Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Yue Lin
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Pu Fang
- Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Shoulin Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Jun Ying
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.,Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China
| | - Xifeng Wang
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
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23
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Smith CJ, Renshaw P, Yurgelun-Todd D, Sheth C. Acute and chronic neuropsychiatric symptoms in novel coronavirus disease 2019 (COVID-19) patients: A qualitative review. Front Public Health 2022; 10:772335. [PMID: 36033820 PMCID: PMC9404694 DOI: 10.3389/fpubh.2022.772335] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 07/11/2022] [Indexed: 01/21/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a global pandemic by the World Health Organization (WHO) on March 11th, 2020. It has had unprecedented adverse effects on healthcare systems, economies, and societies globally. SARS-CoV-2 is not only a threat to physical health but has also been shown to have a severe impact on neuropsychiatric health. Many studies and case reports across countries have demonstrated insomnia, depressed mood, anxiety, post-traumatic stress disorder (PTSD), and cognitive change in COVID-19 patients during the acute phase of the infection, as well as in apparently recovered COVID-19 patients. The goal of this narrative review is to synthesize and summarize the emerging literature detailing the neuropsychiatric manifestations of COVID-19 with special emphasis on the long-term implications of COVID-19.
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Affiliation(s)
- Calen J. Smith
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United States
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, United States
| | - Perry Renshaw
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United States
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, United States
- George E. Wahlen Department of Veterans Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical Center (MIRECC), Salt Lake City, UT, United States
| | - Deborah Yurgelun-Todd
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United States
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, United States
- George E. Wahlen Department of Veterans Affairs Medical Center, VA VISN 19 Mental Illness Research, Education and Clinical Center (MIRECC), Salt Lake City, UT, United States
| | - Chandni Sheth
- Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, United States
- Diagnostic Neuroimaging, University of Utah, Salt Lake City, UT, United States
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24
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Li J, Li L, Liu R, Zhu L, Zhou B, Xiao Y, Hou G, Lin L, Chen X, Peng C. Integrative lipidomic features identify plasma lipid signatures in chronic urticaria. Front Immunol 2022; 13:933312. [PMID: 35967440 PMCID: PMC9370552 DOI: 10.3389/fimmu.2022.933312] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/07/2022] [Indexed: 12/17/2022] Open
Abstract
Chronic urticaria (CU) is a chronic inflammatory skin disease mainly mediated by mast cells. Lipids exert essential functions in biological processes; however, the role of lipids in CU remains unclear. Nontargeted lipidomics was performed to investigate the differential lipid profiles between CU patients and healthy control (HC) subjects. Functional validation studies were performed in vitro and in vivo including β-hexosaminidase release examination from mast cells and passive cutaneous anaphylaxis (PCA) mouse model. We detected dramatically altered glycerophospholipids in CU patients compared with HCs. Phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylglycerol (PG) were increased, while phosphatidylcholine (PC) was reduced in CU patients. The reduction in PC was related to a high weekly urticaria activity score (UAS7), while PS was positively associated with the dermatology life quality index (DLQI). We also identified the differential lipid profiles between chronic spontaneous urticaria (CSU), symptomatic dermographism (SD), and CSU coexist with SD. CU patients were classified into two subtypes (subtype 1 and subtype 2) based on consensus clustering of lipid profiling. Compared with patients in subtype 2, patients in subtype 1 had elevated levels of PC (18:0e/18:2) and PE (38:2), and lower urticaria control test (UCT) scores indicated worse clinical efficiency of secondary generation H1 antihistamines treatment. Importantly, we found that supplementation with PC could attenuate IgE-induced immune responses in mast cells. In general, We described the landscape of plasma lipid alterations in CU patients and provided novel insights into the role of PC in mast cells.
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Affiliation(s)
- Jie Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Liqiao Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Runqiu Liu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lei Zhu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Bingjing Zhou
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yi Xiao
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Guixue Hou
- BGI-Shenzhen, Shenzhen, Guangdong, China
| | - Liang Lin
- BGI-Shenzhen, Shenzhen, Guangdong, China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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25
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Fathi M, Vakili K, Yaghoobpoor S, Qadirifard MS, Kosari M, Naghsh N, Asgari taei A, Klegeris A, Dehghani M, Bahrami A, Taheri H, Mohamadkhani A, Hajibeygi R, Rezaei Tavirani M, Sayehmiri F. Pre-clinical Studies Identifying Molecular Pathways of Neuroinflammation in Parkinson's Disease: A Systematic Review. Front Aging Neurosci 2022; 14:855776. [PMID: 35912090 PMCID: PMC9327618 DOI: 10.3389/fnagi.2022.855776] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 05/23/2022] [Indexed: 12/09/2022] Open
Abstract
Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by neuroinflammation, formation of Lewy bodies, and progressive loss of dopaminergic neurons in the substantia nigra of the brain. In this review, we summarize evidence obtained by animal studies demonstrating neuroinflammation as one of the central pathogenetic mechanisms of PD. We also focus on the protein factors that initiate the development of PD and other neurodegenerative diseases. Our targeted literature search identified 40 pre-clinical in vivo and in vitro studies written in English. Nuclear factor kappa B (NF-kB) pathway is demonstrated as a common mechanism engaged by neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), as well as the bacterial lipopolysaccharide (LPS). The α-synuclein protein, which plays a prominent role in PD neuropathology, may also contribute to neuroinflammation by activating mast cells. Meanwhile, 6-OHDA models of PD identify microsomal prostaglandin E synthase-1 (mPGES-1) as one of the contributors to neuroinflammatory processes in this model. Immune responses are used by the central nervous system to fight and remove pathogens; however, hyperactivated and prolonged immune responses can lead to a harmful neuroinflammatory state, which is one of the key mechanisms in the pathogenesis of PD.
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Affiliation(s)
- Mobina Fathi
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Vakili
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shirin Yaghoobpoor
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Sadegh Qadirifard
- Department of Nursing and Midwifery, Islamic Azad University, Tehran, Iran
- Department of Nursing, Garmsar Branch, Islamic Azad University, Garmsar, Iran
| | - Mohammadreza Kosari
- The First Clinical College, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Navid Naghsh
- Department of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Afsaneh Asgari taei
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Andis Klegeris
- Department of Biology, Faculty of Science, University of British Columbia Okanagan Campus, Kelowna, BC, Canada
| | - Mina Dehghani
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ashkan Bahrami
- Faculty of Medicine, Kashan University of Medical Science, Kashan, Iran
| | - Hamed Taheri
- Dental School, Kazan Federal University, Kazan, Russia
| | - Ashraf Mohamadkhani
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramtin Hajibeygi
- Department of Cardiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mostafa Rezaei Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- *Correspondence: Mostafa Rezaei Tavirani
| | - Fatemeh Sayehmiri
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Fatemeh Sayehmiri
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26
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Xu J, He X, Xu Y, Chen X, Li M, Zhang L, Fu X, Pan M, Wang Q, Hu X. Characteristics of systemic inflammation and brain iron deposition in Parkinson's disease patients. Ann Clin Transl Neurol 2022; 9:276-285. [PMID: 35078271 PMCID: PMC8935274 DOI: 10.1002/acn3.51512] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/04/2021] [Accepted: 01/04/2022] [Indexed: 12/19/2022] Open
Abstract
Objective This study aimed at determining the characteristics of systemic inflammation and brain iron deposition in Parkinson's disease (PD) patients. Methods Thirty two PD patients and 30 gender‐ as well as age‐matched controls were enrolled. Serum interleukin (IL)‐1β, IL‐33, tumor necrosis factor (TNF)‐α, IL‐6, IL‐10, ferritin, iron, and total iron binding capacity (TIBC) levels were assayed. Quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron accumulation in the regions of interest (ROIs). Correlations between concentrations of inflammatory cytokines and biomarkers for peripheral iron metabolism, brain iron deposition were evaluated in the PD group. Results Serum concentrations of IL‐1β and IL‐33 were found to be significantly elevated in the PD group compared to the control group, and in early‐stage PD group compared to advanced‐stage PD group. Total QSM value for bilateral ROIs was significantly elevated in the PD group compared to the control group, and in advanced‐stage PD group compared to early‐stage PD group. There was a significant inverse correlation between serum IL‐1β concentration and total QSM value for bilateral ROIs, between serum ferritin, iron, TIBC concentrations, and total QSM value for bilateral ROIs in PD patients. However, there was no significant correlation between serum IL‐1β concentrations and serum ferritin, iron, TIBC concentrations in PD patients. Interpretation The inflammatory state and chronic brain iron deposition progression in PD patients might be asynchronous. Alterations in systemic inflammation were not correlated with peripheral iron metabolism and might not contribute to the aggravation of brain iron deposition in PD patients.
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Affiliation(s)
- Jinghui Xu
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaofei He
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yunqi Xu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xi Chen
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingyue Li
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liying Zhang
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaodi Fu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mengqiu Pan
- Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou, China
| | - Qun Wang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiquan Hu
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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27
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Chavda V, Singh K, Patel V, Mishra M, Mishra AK. Neuronal Glial Crosstalk: Specific and Shared Mechanisms in Alzheimer’s Disease. Brain Sci 2022; 12:brainsci12010075. [PMID: 35053818 PMCID: PMC8773743 DOI: 10.3390/brainsci12010075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/21/2021] [Accepted: 12/27/2021] [Indexed: 02/04/2023] Open
Abstract
The human brain maintains billions of neurons functional across the lifespan of the individual. The glial, supportive cells of the brain are indispensable to neuron elasticity. They undergo various states (active, reactive, macrophage, primed, resting) and carefully impose either quick repair or the cleaning of injured neurons to avoid damage extension. Identifying the failure of these interactions involving the relation of the input of glial cells to the inception and/or progression of chronic neurodegenerative diseases (ND) is crucial in identifying therapeutic options, given the well-built neuro-immune module of these diseases. In the present review, we scrutinize different interactions and important factors including direct cell–cell contact, intervention by the CD200 system, various receptors present on their surfaces, CXC3RI and TREM2, and chemokines and cytokines with special reference to Alzheimer’s disease (AD). The present review of the available literature will elucidate the contribution of microglia and astrocytes to the pathophysiology of AD, thus evidencing glial cells as obligatory transducers of pathology and superlative targets for interference.
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Affiliation(s)
- Vishal Chavda
- Division of Anesthesia, Dreamzz IVF Center and Women’s Care Hospital, Ahmedabad 382350, Gujarat, India;
| | - Kavita Singh
- Centre for Translational Research, Jiwaji University, Gwalior 474011, Madhya Pradesh, India;
| | - Vimal Patel
- Department of Pharmaceutics, Nirma University, Ahmedabad 382481, Gujarat, India;
| | - Meerambika Mishra
- Department of Infectious Diseases and Pathology, University of Florida, Gainesville, FL 32611, USA
- Correspondence: (M.M.); (A.K.M.)
| | - Awdhesh Kumar Mishra
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongbuk, Korea
- Correspondence: (M.M.); (A.K.M.)
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28
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Ghosh P, Singh R, Ganeshpurkar A, Pokle AV, Singh RB, Singh SK, Kumar A. Cellular and molecular influencers of neuroinflammation in Alzheimer's disease: Recent concepts & roles. Neurochem Int 2021; 151:105212. [PMID: 34656693 DOI: 10.1016/j.neuint.2021.105212] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 09/22/2021] [Accepted: 10/10/2021] [Indexed: 01/21/2023]
Abstract
Alzheimer's disease (AD), an extremely common neurodegenerative disorder of the older generation, is one of the leading causes of death globally. Besides the conventional hallmarks i.e. Amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), neuroinflammation also serves as a major contributing factor in the pathogenesis of AD. There are mounting evidences to support the fundamental role of cellular (microglia, astrocytes, mast cells, and T-cells) and molecular (cytokines, chemokines, caspases, and complement proteins) influencers of neuroinflammation in producing/promoting neurodegeneration and dementia in AD. Genome-wide association studies (GWAS) have revealed the involvement of various single nucleotide polymorphisms (SNPs) of genes related to neuroinflammation with the risk of developing AD. Modulating the release of the neuroinflammatory molecules and targeting their relevant mechanisms may have beneficial effects on the onset, progress and severity of the disease. Here, we review the distinct role of various mediators and modulators of neuroinflammation that impact the pathogenesis and progression of AD as well as incite further research efforts for the treatment of AD through a neuroinflammatory approach.
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Affiliation(s)
- Powsali Ghosh
- Pharmaceutical Chemistry Research Laboratory 1, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India
| | - Ravi Singh
- Pharmaceutical Chemistry Research Laboratory 1, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India
| | - Ankit Ganeshpurkar
- Pharmaceutical Chemistry Research Laboratory 1, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India
| | - Ankit Vyankatrao Pokle
- Pharmaceutical Chemistry Research Laboratory 1, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India
| | - Ravi Bhushan Singh
- Institute of Pharmacy Harischandra PG College, Bawanbigha, Varanasi, India
| | - Sushil Kumar Singh
- Pharmaceutical Chemistry Research Laboratory 1, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India
| | - Ashok Kumar
- Pharmaceutical Chemistry Research Laboratory 1, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005, India.
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Qin B, Peng Y, Zhong C, Cai Y, Zhou S, Chen H, Zhuang J, Zeng H, Xu C, Xu H, Li J, Ying G, Gu C, Chen G, Wang L. Mast Cells Mediate Inflammatory Injury and Aggravate Neurological Impairment in Experimental Subarachnoid Hemorrhage Through Microglial PAR-2 Pathway. Front Cell Neurosci 2021; 15:710481. [PMID: 34646122 PMCID: PMC8503547 DOI: 10.3389/fncel.2021.710481] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 08/19/2021] [Indexed: 11/30/2022] Open
Abstract
Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with high mortality and disability. Aberrant neuroinflammation has been identified as a critical factor accounting for the poor prognosis of SAH patients. Mast cells (MCs), the sentinel cells of the immune system, play a critical in the early immune reactions and participate in multiple pathophysiological process. However, the exact role of MCs on the pathophysiological process after SAH has not been fully understood. The current study was conducted to determine the role of MCs and MC stabilization in the context of SAH. Mouse SAH model was established by endovascular perforation process. Mice received saline or cromolyn (MC stabilizer) or compound 48/80 (MCs degranulator). Post-SAH evaluation included neurobehavioral test, western blot, immunofluorescence, and toluidine blue staining. We demonstrated that SAH induced MCs activation/degranulation. Administration of MC stabilizer cromolyn conferred a better neurologic outcome and decreased brain edema when compared with SAH+vehicle group. Furthermore, cromolyn significantly inhibited neuroinflammatory response and alleviated neuronal damage after SAH. However, pharmacological activation of MCs with compound 48/80 dramatically aggravated SAH-induced brain injury and exacerbated neurologic outcomes. Notably, pharmacological inhibition of microglial PAR-2 significantly reversed MCs-induced inflammatory response and neurological impairment. Additionally, the effect of MCs-derived tryptase in mediating neuroinflammation was also abolished by the microglial PAR-2 blockage in vitro. Taken together, MCs yielded inflammatory injury through activating microglia-related neuroinflammation after SAH. These data shed light on the notion that MCs might be a novel and promising therapeutic target for SAH.
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Affiliation(s)
- Bing Qin
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yucong Peng
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Chen Zhong
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yong Cai
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Shengjun Zhou
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Huaijun Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jianfeng Zhuang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Hanhai Zeng
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Chaoran Xu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Hangzhe Xu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jianru Li
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Guangyu Ying
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Chi Gu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Gao Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Lin Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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30
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Xu C, Li L, Wang C, Jiang J, Li L, Zhu L, Jin S, Jin Z, Lee JJ, Li G, Yan G. Effects of G-Rh2 on mast cell-mediated anaphylaxis via AKT-Nrf2/NF-κB and MAPK-Nrf2/NF-κB pathways. J Ginseng Res 2021; 46:550-560. [PMID: 35818417 PMCID: PMC9270651 DOI: 10.1016/j.jgr.2021.10.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/04/2021] [Accepted: 10/04/2021] [Indexed: 11/18/2022] Open
Abstract
Background The effect of ginsenoside Rh2 (G-Rh2) on mast cell-mediated anaphylaxis remains unclear. Herein, we investigated the effects of G-Rh2 on OVA-induced asthmatic mice and on mast cell-mediated anaphylaxis. Methods Asthma model was established for evaluating airway changes and ear allergy. RPMCs and RBL-2H3 were used for in vitro experiments. Calcium uptake, histamine release and degranulation were detected. ELISA and Western blot measured cytokine and protein levels, respectively. Results G-Rh2 inhibited OVA-induced airway remodeling, the production of TNF-α, IL-4, IL-8, IL-1β and the degranulation of mast cells of asthmatic mice. G-Rh2 inhibited the activation of Syk and Lyn in lung tissue of OVA-induced asthmatic mice. G-Rh2 inhibited serum IgE production in OVA induced asthmatic mice. Furthermore, G-Rh2 reduced the ear allergy in IgE-sensitized mice. G-Rh2 decreased the ear thickness. In vitro experiments G-Rh2 significantly reduced calcium uptake and inhibited histamine release and degranulation in RPMCs. In addition, G-Rh2 reduced the production of IL-1β, TNF-α, IL-8, and IL-4 in IgE-sensitized RBL-2H3 cells. Interestingly, G-Rh2 was involved in the FcεRI pathway activation of mast cells and the transduction of the Lyn/Syk signaling pathway. G-Rh2 inhibited PI3K activity in a dose-dependent manner. By blocking the antigen-induced phosphorylation of Lyn, Syk, LAT, PLCγ2, PI3K ERK1/2 and Raf-1 expression, G-Rh2 inhibited the NF-κB, AKT-Nrf2, and p38MAPK-Nrf2 pathways. However, G-Rh2 up-regulated Keap-1 expression. Meanwhile, G-Rh2 reduced the levels of p-AKT, p38MAPK and Nrf2 in RBL-2H3 sensitized IgE cells and inhibited NF-κB signaling pathway activation by activating the AKT-Nrf2 and p38MAPK-Nrf2 pathways. Conclusion G-Rh2 inhibits mast cell-induced allergic inflammation, which might be mediated by the AKT-Nrf2/NF-κB and p38MAPK-Nrf2/NF-κB signaling pathways.
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Affiliation(s)
- Chang Xu
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, China
- Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, Yanji, China
| | - Liangchang Li
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, China
- Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, Yanji, China
| | - Chongyang Wang
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, China
- Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, Yanji, China
| | - Jingzhi Jiang
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, China
- Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, Yanji, China
| | - Li Li
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, China
- Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, Yanji, China
| | - Lianhua Zhu
- Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, Yanji, China
- Department of Dermatology, Yanbian University Hospital, Yanji, China
| | - Shan Jin
- Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, Yanji, China
- Department of Dermatology, Yanbian University Hospital, Yanji, China
| | - Zhehu Jin
- Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, Yanji, China
- Department of Dermatology, Yanbian University Hospital, Yanji, China
| | - Jung Joon Lee
- College of Pharmacy, Yanbian University, Yanji, China
| | - Guanhao Li
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, China
- Food Research Center of Yanbian University, Yanji, China
- Corresponding author. Food Research Center of Yanbian University, No. 977 Gongyuan Road, Yanji, 133002, PR China.
| | - Guanghai Yan
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, China
- Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, Yanji, China
- Corresponding author. Department of Anatomy, Histology and Embryology, Medical College, Yanbian University, No. 977 Gongyuan Road, Yanji, 133002, PR China.
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Yeung SSH, Ho YS, Chang RCC. The role of meningeal populations of type II innate lymphoid cells in modulating neuroinflammation in neurodegenerative diseases. Exp Mol Med 2021; 53:1251-1267. [PMID: 34489558 PMCID: PMC8492689 DOI: 10.1038/s12276-021-00660-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/28/2021] [Accepted: 06/30/2021] [Indexed: 02/08/2023] Open
Abstract
Recent research into meningeal lymphatics has revealed a never-before appreciated role of type II innate lymphoid cells (ILC2s) in modulating neuroinflammation in the central nervous system (CNS). To date, the role of ILC2-mediated inflammation in the periphery has been well studied. However, the exact distribution of ILC2s in the CNS and therefore their putative role in modulating neuroinflammation in neurodegenerative diseases such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and major depressive disorder (MDD) remain highly elusive. Here, we review the current evidence of ILC2-mediated modulation of neuroinflammatory cues (i.e., IL-33, IL-25, IL-5, IL-13, IL-10, TNFα, and CXCL16-CXCR6) within the CNS, highlight the distribution of ILC2s in both the periphery and CNS, and discuss some challenges associated with cell type-specific targeting that are important for therapeutics. A comprehensive understanding of the roles of ILC2s in mediating and responding to inflammatory cues may provide valuable insight into potential therapeutic strategies for many dementia-related disorders.
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Affiliation(s)
- Sherry Sin-Hang Yeung
- grid.194645.b0000000121742757Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China
| | - Yuen-Shan Ho
- grid.16890.360000 0004 1764 6123School of Nursing, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR China
| | - Raymond Chuen-Chung Chang
- grid.194645.b0000000121742757Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR China ,grid.194645.b0000000121742757State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR China
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Carthy E, Ellender T. Histamine, Neuroinflammation and Neurodevelopment: A Review. Front Neurosci 2021; 15:680214. [PMID: 34335160 PMCID: PMC8317266 DOI: 10.3389/fnins.2021.680214] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/18/2021] [Indexed: 12/16/2022] Open
Abstract
The biogenic amine, histamine, has been shown to critically modulate inflammatory processes as well as the properties of neurons and synapses in the brain, and is also implicated in the emergence of neurodevelopmental disorders. Indeed, a reduction in the synthesis of this neuromodulator has been associated with the disorders Tourette's syndrome and obsessive-compulsive disorder, with evidence that this may be through the disruption of the corticostriatal circuitry during development. Furthermore, neuroinflammation has been associated with alterations in brain development, e.g., impacting synaptic plasticity and synaptogenesis, and there are suggestions that histamine deficiency may leave the developing brain more vulnerable to proinflammatory insults. While most studies have focused on neuronal sources of histamine it remains unclear to what extent other (non-neuronal) sources of histamine, e.g., from mast cells and other sources, can impact brain development. The few studies that have started exploring this in vitro, and more limited in vivo, would indicate that non-neuronal released histamine and other preformed mediators can influence microglial-mediated neuroinflammation which can impact brain development. In this Review we will summarize the state of the field with regard to non-neuronal sources of histamine and its impact on both neuroinflammation and brain development in key neural circuits that underpin neurodevelopmental disorders. We will also discuss whether histamine receptor modulators have been efficacious in the treatment of neurodevelopmental disorders in both preclinical and clinical studies. This could represent an important area of future research as early modulation of histamine from neuronal as well as non-neuronal sources may provide novel therapeutic targets in these disorders.
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Affiliation(s)
- Elliott Carthy
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Tommas Ellender
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
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33
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Sun Y, Wen Y, Wang L, Wen L, You W, Wei S, Mao L, Wang H, Chen Z, Yang X. Therapeutic Opportunities of Interleukin-33 in the Central Nervous System. Front Immunol 2021; 12:654626. [PMID: 34079543 PMCID: PMC8165230 DOI: 10.3389/fimmu.2021.654626] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 05/04/2021] [Indexed: 01/14/2023] Open
Abstract
Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is involved in various diseases. IL-33 exerts its effects via its heterodimeric receptor complex, which comprises suppression of tumorigenicity 2 (ST2) and the IL-1 receptor accessory protein (IL-1RAP). Increasing evidence has demonstrated that IL-33/ST2 signaling plays diverse but crucial roles in the homeostasis of the central nervous system (CNS) and the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infection, trauma, and ischemic stroke. In the current review, we focus on the functional roles and cellular signaling mechanisms of IL-33 in the CNS and evaluate the potential for diagnostic and therapeutic applications.
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Affiliation(s)
- Yun Sun
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Yankai Wen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Luxi Wang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang Wen
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Wendong You
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Shuang Wei
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Lin Mao
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Hao Wang
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Zuobing Chen
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Xiaofeng Yang
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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Pham L, Baiocchi L, Kennedy L, Sato K, Meadows V, Meng F, Huang CK, Kundu D, Zhou T, Chen L, Alpini G, Francis H. The interplay between mast cells, pineal gland, and circadian rhythm: Links between histamine, melatonin, and inflammatory mediators. J Pineal Res 2021; 70:e12699. [PMID: 33020940 PMCID: PMC9275476 DOI: 10.1111/jpi.12699] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/18/2020] [Accepted: 09/26/2020] [Indexed: 12/14/2022]
Abstract
Our daily rhythmicity is controlled by a circadian clock with a specific set of genes located in the suprachiasmatic nucleus in the hypothalamus. Mast cells (MCs) are major effector cells that play a protective role against pathogens and inflammation. MC distribution and activation are associated with the circadian rhythm via two major pathways, IgE/FcεRI- and IL-33/ST2-mediated signaling. Furthermore, there is a robust oscillation between clock genes and MC-specific genes. Melatonin is a hormone derived from the amino acid tryptophan and is produced primarily in the pineal gland near the center of the brain, and histamine is a biologically active amine synthesized from the decarboxylation of the amino acid histidine by the L-histidine decarboxylase enzyme. Melatonin and histamine are previously reported to modulate circadian rhythms by pathways incorporating various modulators in which the nuclear factor-binding near the κ light-chain gene in B cells, NF-κB, is the common key factor. NF-κB interacts with the core clock genes and disrupts the production of pro-inflammatory cytokine mediators such as IL-6, IL-13, and TNF-α. Currently, there has been no study evaluating the interdependence between melatonin and histamine with respect to circadian oscillations in MCs. Accumulating evidence suggests that restoring circadian rhythms in MCs by targeting melatonin and histamine via NF-κB may be promising therapeutic strategy for MC-mediated inflammatory diseases. This review summarizes recent findings for circadian-mediated MC functional roles and activation paradigms, as well as the therapeutic potentials of targeting circadian-mediated melatonin and histamine signaling in MC-dependent inflammatory diseases.
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Affiliation(s)
- Linh Pham
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Science and Mathematics, Texas A&M University – Central Texas, Killeen, TX, USA
| | | | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Fanyin Meng
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chiung-Kuei Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medicine, Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN, USA
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Zhang X, Shao Z, Xu S, Liu Q, Liu C, Luo Y, Jin L, Li S. Immune Profiling of Parkinson's Disease Revealed Its Association With a Subset of Infiltrating Cells and Signature Genes. Front Aging Neurosci 2021; 13:605970. [PMID: 33633562 PMCID: PMC7899990 DOI: 10.3389/fnagi.2021.605970] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 01/19/2021] [Indexed: 11/25/2022] Open
Abstract
Parkinson’s disease (PD) is an age-related and second most common neurodegenerative disorder. In recent years, increasing evidence revealed that peripheral immune cells might be able to infiltrate into brain tissues, which could arouse neuroinflammation and aggravate neurodegeneration. This study aimed to illuminate the landscape of peripheral immune cells and signature genes associated with immune infiltration in PD. Several transcriptomic datasets of substantia nigra (SN) from the Gene Expression Omnibus (GEO) database were separately collected as training cohort, testing cohort, and external validation cohort. The immunoscore of each sample calculated by single-sample gene set enrichment analysis was used to reflect the peripheral immune cell infiltration and to identify the differential immune cell types between PD and healthy participants. According to receiver operating characteristic (ROC) curve analysis, the immunoscore achieved an overall accuracy of the area under the curve (AUC) = 0.883 in the testing cohort, respectively. The immunoscore displayed good performance in the external validation cohort with an AUC of 0.745. The correlation analysis and logistic regression analysis were used to analyze the correlation between immune cells and PD, and mast cell was identified most associated with the occurrence of PD. Additionally, increased mast cells were also observed in our in vivo PD model. Weighted gene co-expression network analysis (WGCNA) was used to selected module genes related to a mast cell. The least absolute shrinkage and selection operator (LASSO) analysis and random-forest analysis were used to analyze module genes, and two hub genes RBM3 and AGTR1 were identified as associated with mast cells in the training cohort. The expression levels of RBM3 and AGTR1 in these cohorts and PD models revealed that these hub genes were significantly downregulated in PD. Moreover, the expression trend of the aforementioned two genes differed in mast cells and dopaminergic (DA) neurons. In conclusion, this study not only exhibited a landscape of immune infiltrating patterns in PD but also identified mast cells and two hub genes associated with the occurrence of PD, which provided potential therapeutic targets for PD patients (PDs).
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Affiliation(s)
- Xi Zhang
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhihua Shao
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Sutong Xu
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiulu Liu
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chenming Liu
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuping Luo
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lingjing Jin
- Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Siguang Li
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.,Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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Sandhu JK, Kulka M. Decoding Mast Cell-Microglia Communication in Neurodegenerative Diseases. Int J Mol Sci 2021; 22:ijms22031093. [PMID: 33499208 PMCID: PMC7865982 DOI: 10.3390/ijms22031093] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/16/2021] [Accepted: 01/17/2021] [Indexed: 12/12/2022] Open
Abstract
Microglia, resident immune cells of the central nervous system (CNS), play a pivotal role in immune surveillance and maintenance of neuronal health. Mast cells are also important resident immune cells of the CNS but they are underappreciated and understudied. Both microglia and mast cells are endowed with an array of signaling receptors that recognize microbes and cellular damage. As cellular sensors and effectors in the CNS, they respond to many CNS perturbations and have been implicated in neuroinflammation and neurodegeneration. Mast cells contain numerous secretory granules packaged with a plethora of readily available and newly synthesized compounds known as 'mast cell mediators'. Mast cells act as 'first responders' to a pathogenic stimuli and respond by degranulation and releasing these mediators into the extracellular milieu. They alert other glial cells, including microglia to initiate neuroinflammatory processes that culminate in the resolution of injury. However, failure to resolve the pathogenic process can lead to persistent activation, release of pro-inflammatory mediators and amplification of neuroinflammatory responses, in turn, resulting in neuronal dysfunction and demise. This review discusses the current understanding of the molecular conversation between mast cells and microglia in orchestrating immune responses during two of the most prevalent neurodegenerative diseases, namely Alzheimer's disease and Parkinson's disease. Here we also survey the potential emerging therapeutic approaches targeting common pathways in mast cells and microglia to extinguish the fire of inflammation.
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Affiliation(s)
- Jagdeep K. Sandhu
- Human Health Therapeutics Research Centre, National Research Council Canada, 1200 Montreal Road, Ottawa, ON K1A 0R6, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Correspondence: (J.K.S.); (M.K.); Tel.: +1-613-993-5304 (J.K.S.); +1-780-641-1687 (M.K.)
| | - Marianna Kulka
- Nanotechnology Research Centre, National Research Council Canada, 11421 Saskatchewan Drive, Edmonton, AB T6G 2M9, Canada
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Correspondence: (J.K.S.); (M.K.); Tel.: +1-613-993-5304 (J.K.S.); +1-780-641-1687 (M.K.)
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Grigorev IP, Korzhevskii DE. Mast Cells in the Vertebrate Brain:
Localization and Functions. J EVOL BIOCHEM PHYS+ 2021. [DOI: 10.1134/s0022093021010026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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38
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Yuan LJ, Zhang M, Chen S, Chen WF. Anti-inflammatory effect of IGF-1 is mediated by IGF-1R cross talk with GPER in MPTP/MPP +-induced astrocyte activation. Mol Cell Endocrinol 2021; 519:111053. [PMID: 33035625 DOI: 10.1016/j.mce.2020.111053] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 10/02/2020] [Accepted: 10/04/2020] [Indexed: 12/17/2022]
Abstract
Insulin-like growth factor-1 (IGF-1) is a potent neuroprotective polypeptide that exerts neuroprotective effects via the IGF-1 receptor (IGF-1R). Our previous study reported that G protein-coupled estrogen receptor (GPER) was involved in the anti-apoptotic effect of IGF-1. The present study was designed to investigate the anti-inflammatory effect of IGF-1 in association with astrocyte activation and the molecular details of the interaction between IGF-1R and GPER. We showed that IGF-1 could improve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor deficits and attenuate the upregulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) both in vivo and in vitro. The IGF-1R antagonist JB-1 and the GPER antagonist G15 could antagonize the anti-inflammatory effect of IGF-1. Silencing GPER abrogated the inhibitory effect of IGF-1 on 1-methyl-4-phenylpyridinium (MPP+)-induced upregulation of COX-2 and iNOS in primary astrocytes. Moreover, the MPP + -induced inflammatory response was related to the activation of mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways. The inhibitory effects of IGF-1 on the phosphorylation of p38, JNK and IκB could be blocked by JB-1. G15 antagonized the inhibitory effects of IGF-1 on p-JNK and p-IκB, but not p-p38. Furthermore, IGF-1 treatment alone increased the expression of GPER, which was blocked by JB-1, the phosphatidylinositol 3-kinase (PI3-K) antagonist LY294002 and the MEK antagonist PD98059 in primary astrocytes. Overall, we show for the first time that GPER may contribute to the anti-inflammatory effect of IGF-1 against MPTP/MPP + -induced astrocyte activation. IGF-1 could regulate the expression of GPER via the IGF-1R/PI3-K/MAPK signaling pathway in primary astrocytes.
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MESH Headings
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- 1-Methyl-4-phenylpyridinium/toxicity
- Animals
- Anti-Inflammatory Agents/pharmacology
- Astrocytes/drug effects
- Astrocytes/metabolism
- Behavior, Animal
- Benzodioxoles/pharmacology
- Cells, Cultured
- Cyclooxygenase 2/genetics
- Cyclooxygenase 2/metabolism
- Humans
- Insulin-Like Growth Factor I/pharmacology
- MAP Kinase Signaling System/drug effects
- Male
- Mice, Inbred C57BL
- NF-kappa B/metabolism
- Nitric Oxide Synthase Type II/genetics
- Nitric Oxide Synthase Type II/metabolism
- Phosphatidylinositol 3-Kinases/metabolism
- Phosphorylation/drug effects
- Quinolines/pharmacology
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptor, IGF Type 1/metabolism
- Receptors, Estrogen/metabolism
- Receptors, G-Protein-Coupled/metabolism
- Substantia Nigra/metabolism
- Up-Regulation/drug effects
- Mice
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Affiliation(s)
- Liang-Jie Yuan
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China; School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, China
| | - Mei Zhang
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Su Chen
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Wen-Fang Chen
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
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Zhang Y, Wang J, Ge S, Zeng Y, Wang N, Wu Y. Roxithromycin inhibits compound 48/80-induced pseudo-allergy via the MrgprX2 pathway both in vitro and in vivo. Cell Immunol 2020; 358:104239. [PMID: 33129497 DOI: 10.1016/j.cellimm.2020.104239] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 10/04/2020] [Accepted: 10/08/2020] [Indexed: 12/19/2022]
Abstract
Roxithromycin (ROX) is a macrolide antibiotic with a variety of immunological effects. Mast cells (MCs) play a key role in host defense, mediating hypersensitivity and pseudo-allergic reactions. Mas-related G protein-coupled receptor X2 (MrgprX2) is the main receptor related to pseudo-allergy. In this study, we investigated the anti-pseudo-allergy effect of ROX and its underlying mechanism. The effects of ROX on passive cutaneous anaphylaxis (PCA) and active systemic allergy were examined, degranulation, Ca2+ influx, and cytokine release were studied in vivo and in vitro. Interactions between ROX and MrgprX2 protein were also detected through surface plasmon resonance. The PCA and active systemic allergy induced by compound 48/80 were inhibited by ROX. An intermolecular interaction was detected between the ROX and MrgprX2 protein. In conclusion, ROX could inhibit pseudo-allergic reactions, and this effect involves the Ca2+/PLC/IP3 pathway of MrgprX2. This study provides new insight into the anti-pseudo-allergy effects of ROX.
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Affiliation(s)
- Yongjing Zhang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Jue Wang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Shuai Ge
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Yingnan Zeng
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Nan Wang
- School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.
| | - Yuanyuan Wu
- The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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40
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Kempuraj D, Ahmed ME, Selvakumar GP, Thangavel R, Raikwar SP, Zaheer SA, Iyer SS, Govindarajan R, Nattanmai Chandrasekaran P, Burton C, James D, Zaheer A. Acute Traumatic Brain Injury-Induced Neuroinflammatory Response and Neurovascular Disorders in the Brain. Neurotox Res 2020; 39:359-368. [PMID: 32955722 PMCID: PMC7502806 DOI: 10.1007/s12640-020-00288-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/12/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023]
Abstract
Acute traumatic brain injury (TBI) leads to neuroinflammation, neurodegeneration, cognitive decline, psychological disorders, increased blood-brain barrier (BBB) permeability, and microvascular damage in the brain. Inflammatory mediators secreted from activated glial cells, neurons, and mast cells are implicated in the pathogenesis of TBI through secondary brain damage. Abnormalities or damage to the neurovascular unit is the indication of secondary injuries in the brain after TBI. However, the precise mechanisms of molecular and ultrastructural neurovascular alterations involved in the pathogenesis of acute TBI are not yet clearly understood. Moreover, currently, there are no precision-targeted effective treatment options to prevent the sequelae of TBI. In this study, mice were subjected to closed head weight-drop-induced acute TBI and evaluated neuroinflammatory and neurovascular alterations in the brain by immunofluorescence staining or quantitation by enzyme-linked immunosorbent assay (ELISA) procedure. Mast cell stabilizer drug cromolyn was administered to inhibit the neuroinflammatory response of TBI. Results indicate decreased level of pericyte marker platelet-derived growth factor receptor-beta (PDGFR-β) and BBB-associated tight junction proteins junctional adhesion molecule-A (JAM-A) and zonula occludens-1 (ZO-1) in the brains 7 days after weight-drop-induced acute TBI as compared with the brains from sham control mice indicating acute TBI-associated BBB/tight junction protein disruption. Further, the administration of cromolyn drug significantly inhibited acute TBI-associated decrease of PDGFR-β, JAM-A, and ZO-1 in the brain. These findings suggest that acute TBI causes BBB/tight junction damage and that cromolyn administration could protect this acute TBI-induced brain damage as well as its long-time consequences.
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Affiliation(s)
- Duraisamy Kempuraj
- Department of Neurology, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA. .,The Center for Translational Neuroscience, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA. .,Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.
| | - Mohammad Ejaz Ahmed
- Department of Neurology, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,The Center for Translational Neuroscience, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Govindhasamy Pushpavathi Selvakumar
- Department of Neurology, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,The Center for Translational Neuroscience, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Ramasamy Thangavel
- Department of Neurology, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,The Center for Translational Neuroscience, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Sudhanshu P Raikwar
- Department of Neurology, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,The Center for Translational Neuroscience, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Smita A Zaheer
- Department of Neurology, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,The Center for Translational Neuroscience, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA
| | - Shankar S Iyer
- Department of Neurology, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,The Center for Translational Neuroscience, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA.,Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Raghav Govindarajan
- Department of Neurology, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA
| | | | | | | | - Asgar Zaheer
- Department of Neurology, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA. .,The Center for Translational Neuroscience, School of Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO, USA. .,Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.
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41
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Ren H, Han R, Chen X, Liu X, Wan J, Wang L, Yang X, Wang J. Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update. J Cereb Blood Flow Metab 2020; 40:1752-1768. [PMID: 32423330 PMCID: PMC7446569 DOI: 10.1177/0271678x20923551] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and disability but no specific or effective treatment. In the last two decades, much has been learned about the pathologic mechanisms of ICH. It is now known that after ICH onset, immune and inflammatory responses contribute to blood-brain barrier disruption, edema development, and cell death processes, jointly resulting in secondary brain injury. However, the translation of potential therapies from preclinical to clinical success has been disappointing. With the development of new laboratory technology, recent progress has been made in the understanding of ICH pathomechanisms, and promising therapeutic targets have been identified. This review provides an update of recent progress on ICH and describes the prospects for further preclinical studies in this field. Our goal is to discuss new therapeutic targets and directions for the treatment of ICH and promote the effective transformation from preclinical to clinical trials.
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Affiliation(s)
- Honglei Ren
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ranran Han
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Xuemei Chen
- Department of Human Anatomy, Basic Medical College of Zhengzhou University, Zhengzhou, China
| | - Xi Liu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jieru Wan
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Limin Wang
- Department of Neurology, Guangdong Neuroscience Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiuli Yang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jian Wang
- Department of Human Anatomy, Basic Medical College of Zhengzhou University, Zhengzhou, China
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42
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Selvakumar GP, Ahmed ME, Thangavel R, Kempuraj D, Dubova I, Raikwar SP, Zaheer S, Iyer SS, Zaheer A. A role for glia maturation factor dependent activation of mast cells and microglia in MPTP induced dopamine loss and behavioural deficits in mice. Brain Behav Immun 2020; 87:429-443. [PMID: 31982500 PMCID: PMC7316620 DOI: 10.1016/j.bbi.2020.01.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/15/2020] [Accepted: 01/17/2020] [Indexed: 12/23/2022] Open
Abstract
The molecular mechanism mediating degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) is not yet fully understood. Previously, we have shown the contribution of glia maturation factor (GMF), a proinflammatory protein in dopaminergic neurodegeneration mediated by activation of mast cells (MCs). In this study, methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal neurodegeneration and astro-glial activations were determined by western blot and immunofluorescence techniques in wild type (WT) mice, MC-deficient (MC-KO) mice and GMF-deficient (GMF-KO) mice, with or without MC reconstitution before MPTP administration. We show that GMF-KO in the MCs reduces the synergistic effects of MC and Calpain1 (calcium-activated cysteine protease enzyme)-dependent dopaminergic neuronal loss that reduces motor behavioral impairments in MPTP-treated mouse. Administration of MPTP increase in calpain-mediated proteolysis in nigral dopaminergic neurons further resulting in motor decline in mice. We found that MPTP administered WT mice exhibits oxidative stress due to significant increases in the levels of malondialdehyde, superoxide dismutase and reduction in the levels of reduced glutathione and glutathione peroxidase activity as compared with both MC-KO and GMF-KO mice. The number of TH-positive neurons in the ventral tegmental area, substantia nigra and the fibers in the striatum were significantly reduced while granulocyte macrophage colony-stimulating factor (GM-CSF), MC-Tryptase, GFAP, IBA1, Calpain1 and intracellular adhesion molecule 1 expression were significantly increased in WT mice. Similarly, tyrosine hydroxylase, dopamine transporters and vesicular monoamine transporters 2 proteins expression were significantly reduced in the SN of MPTP treated WT mice. The motor behavior as analyzed by rotarod and hang test was significantly reduced in WT mice as compared with both the MC-KO and GMF-KO mice. We conclude that GMF-dependent MC activation enhances the detrimental effect of astro-glial activation-mediated oxidative stress and neuroinflammation in the midbrain, and its inhibition may slowdown the progression of PD.
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Affiliation(s)
- Govindhasamy Pushpavathi Selvakumar
- Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65211, United States,Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65211, United States
| | - Mohammad Ejaz Ahmed
- Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65211, United States,Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65211, United States
| | - Ramasamy Thangavel
- Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65211, United States,Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65211, United States
| | - Duraisamy Kempuraj
- Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65211, United States,Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65211, United States
| | - Iuliia Dubova
- Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65211, United States
| | - Sudhanshu P. Raikwar
- Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65211, United States,Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65211, United States
| | - Smita Zaheer
- Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65211, United States
| | - Shankar S. Iyer
- Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65211, United States,Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65211, United States
| | - Asgar Zaheer
- Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65211, United States; Department of Neurology, and Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65211, United States.
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Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury. Mediators Inflamm 2020; 2020:4243953. [PMID: 32684835 PMCID: PMC7333064 DOI: 10.1155/2020/4243953] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/28/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023] Open
Abstract
Traumatic brain injury (TBI) is one of the major health problems worldwide that causes death or permanent disability through primary and secondary damages in the brain. TBI causes primary brain damage and activates glial cells and immune and inflammatory cells, including mast cells in the brain associated with neuroinflammatory responses that cause secondary brain damage. Though the survival rate and the neurological deficiencies have shown significant improvement in many TBI patients with newer therapeutic options, the underlying pathophysiology of TBI-mediated neuroinflammation, neurodegeneration, and cognitive dysfunctions is understudied. In this study, we analyzed mast cells and neuroinflammation in weight drop-induced TBI. We analyzed mast cell activation by toluidine blue staining, serum chemokine C-C motif ligand 2 (CCL2) level by enzyme-linked immunosorbent assay (ELISA), and proteinase-activated receptor-2 (PAR-2), a mast cell and inflammation-associated protein, vascular endothelial growth factor receptor 2 (VEGFR2), and blood-brain barrier tight junction-associated claudin 5 and Zonula occludens-1 (ZO-1) protein expression in the brains of TBI mice. Mast cell activation and its numbers increased in the brains of 24 h and 72 h TBI when compared with sham control brains without TBI. Mouse brains after TBI show increased CCL2, PAR-2, and VEGFR2 expression and derangement of claudin 5 and ZO-1 expression as compared with sham control brains. TBI can cause mast cell activation, neuroinflammation, and derangement of tight junction proteins associated with increased BBB permeability. We suggest that inhibition of mast cell activation can suppress neuroimmune responses and glial cell activation-associated neuroinflammation and neurodegeneration in TBI.
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Kempuraj D, Ahmed ME, Selvakumar GP, Thangavel R, Raikwar SP, Zaheer SA, Iyer SS, Burton C, James D, Zaheer A. Psychological Stress-Induced Immune Response and Risk of Alzheimer's Disease in Veterans from Operation Enduring Freedom and Operation Iraqi Freedom. Clin Ther 2020; 42:974-982. [PMID: 32184013 PMCID: PMC7308186 DOI: 10.1016/j.clinthera.2020.02.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/19/2020] [Accepted: 02/22/2020] [Indexed: 12/26/2022]
Abstract
PURPOSE Psychological stress is a significant health problem in veterans and their family members. Traumatic brain injury (TBI) and stress lead to the onset, progression, and worsening of several inflammatory and neurodegenerative diseases in veterans and civilians. Alzheimer's disease (AD) is a progressive, irreversible neuroinflammatory disease that causes problems with memory, thinking, and behavior. TBIs and chronic psychological stress cause and accelerate the pathology of neuroinflammatory diseases such as AD. However, the precise molecular and cellular mechanisms governing neuroinflammation and neurodegeneration are currently unknown, especially in veterans. The purpose of this review article was to advance the hypothesis that stress and TBI-mediated immune response substantially contribute and accelerate the pathogenesis of AD in veterans and their close family members and civilians. METHODS The information in this article was collected and interpreted from published articles in PubMed between 1985 and 2020 using the key words stress, psychological stress, Afghanistan war, Operation Enduring Freedom (OEF), Iraq War, Operation Iraqi Freedom (OIF), Operation New Dawn (OND), traumatic brain injury, mast cell and stress, stress and neuroimmune response, stress and Alzheimer's disease, traumatic brain injury, and Alzheimer's disease. FINDINGS Chronic psychological stress and brain injury induce the generation and accumulation of beta-amyloid peptide, amyloid plaques, neurofibrillary tangles, and phosphorylation of tau in the brain, thereby contributing to AD pathogenesis. Active military personnel and veterans are under enormous psychological stress due to various war-related activities, including TBIs, disabilities, fear, new environmental conditions, lack of normal life activities, insufficient communications, explosions, military-related noise, and health hazards. Brain injury, stress, mast cell, and other immune cell activation can induce headache, migraine, dementia, and upregulate neuroinflammation and neurodegeneration in veterans of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn. TBIs, posttraumatic stress disorder, psychological stress, pain, glial activation, and dementia in active military personnel, veterans, or their family members can cause AD several years later in their lives. We suggest that there are increasing numbers of veterans with TBIs and stress and that these veterans may develop AD late in life if no appropriate therapeutic intervention is available. IMPLICATIONS Per these published reports, the fact that TBIs and psychological stress can accelerate the pathogenesis of AD should be recognized. Active military personnel, veterans, and their close family members should be evaluated regularly for stress symptoms to prevent the pathogenesis of neurodegenerative diseases, including AD.
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Affiliation(s)
- Duraisamy Kempuraj
- Harry S. Truman Memorial Veterans Hospital, US Department of Veterans Affairs, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA; Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA.
| | - Mohammad Ejaz Ahmed
- Harry S. Truman Memorial Veterans Hospital, US Department of Veterans Affairs, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA; Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Govindhasamy Pushpavathi Selvakumar
- Harry S. Truman Memorial Veterans Hospital, US Department of Veterans Affairs, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA; Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Ramasamy Thangavel
- Harry S. Truman Memorial Veterans Hospital, US Department of Veterans Affairs, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA; Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Sudhanshu P Raikwar
- Harry S. Truman Memorial Veterans Hospital, US Department of Veterans Affairs, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA; Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Smita A Zaheer
- Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA; Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Shankar S Iyer
- Harry S. Truman Memorial Veterans Hospital, US Department of Veterans Affairs, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA; Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | | | | | - Asgar Zaheer
- Harry S. Truman Memorial Veterans Hospital, US Department of Veterans Affairs, Columbia, MO, USA; Department of Neurology, School of Medicine, University of Missouri, Columbia, MO, USA; Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA.
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45
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Song Y, Lu M, Yuan H, Chen T, Han X. Mast cell-mediated neuroinflammation may have a role in attention deficit hyperactivity disorder (Review). Exp Ther Med 2020; 20:714-726. [PMID: 32742317 PMCID: PMC7388140 DOI: 10.3892/etm.2020.8789] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 04/29/2020] [Indexed: 12/12/2022] Open
Abstract
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental and behavioral disorder with a serious negative impact on the quality of life from childhood until adulthood, which may cause academic failure, family disharmony and even social unrest. The pathogenesis of ADHD has remained to be fully elucidated, leading to difficulties in the treatment of this disease. Genetic and environmental factors contribute to the risk of ADHD development. Certain studies indicated that ADHD has high comorbidity with allergic and autoimmune diseases, with various patients with ADHD having a high inflammatory status. Increasing evidence indicated that mast cells (MCs) are involved in the pathogenesis of brain inflammation and neuropsychiatric disorders. MCs may cause or aggravate neuroinflammation via the selective release of inflammatory factors, interaction with glial cells and neurons, activation of the hypothalamic-pituitary adrenal axis or disruption of the blood-brain barrier integrity. In the present review, the notion that MC activation may be involved in the occurrence and development of ADHD through a number of ways is discussed based on previously published studies. The association between MCs and ADHD appears to lack sufficient evidence at present and this hypothesis is considered to be worthy of further study, providing a novel perspective for the treatment of ADHD.
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Affiliation(s)
- Yuchen Song
- Institute of Pediatrics of Traditional Chinese Medicine, First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Manqi Lu
- Institute of Pediatrics of Traditional Chinese Medicine, First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Haixia Yuan
- Institute of Pediatrics of Traditional Chinese Medicine, First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Tianyi Chen
- Institute of Pediatrics of Traditional Chinese Medicine, First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Xinmin Han
- Institute of Pediatrics of Traditional Chinese Medicine, First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
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Kempuraj D, Ahmed ME, Selvakumar GP, Thangavel R, Dhaliwal AS, Dubova I, Mentor S, Premkumar K, Saeed D, Zahoor H, Raikwar SP, Zaheer S, Iyer SS, Zaheer A. Brain Injury-Mediated Neuroinflammatory Response and Alzheimer's Disease. Neuroscientist 2020; 26:134-155. [PMID: 31092147 PMCID: PMC7274851 DOI: 10.1177/1073858419848293] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Traumatic brain injury (TBI) is a major health problem in the United States, which affects about 1.7 million people each year. Glial cells, T-cells, and mast cells perform specific protective functions in different regions of the brain for the recovery of cognitive and motor functions after central nervous system (CNS) injuries including TBI. Chronic neuroinflammatory responses resulting in neuronal death and the accompanying stress following brain injury predisposes or accelerates the onset and progression of Alzheimer's disease (AD) in high-risk individuals. About 5.7 million Americans are currently living with AD. Immediately following brain injury, mast cells respond by releasing prestored and preactivated mediators and recruit immune cells to the CNS. Blood-brain barrier (BBB), tight junction and adherens junction proteins, neurovascular and gliovascular microstructural rearrangements, and dysfunction associated with increased trafficking of inflammatory mediators and inflammatory cells from the periphery across the BBB leads to increase in the chronic neuroinflammatory reactions following brain injury. In this review, we advance the hypothesis that neuroinflammatory responses resulting from mast cell activation along with the accompanying risk factors such as age, gender, food habits, emotional status, stress, allergic tendency, chronic inflammatory diseases, and certain drugs can accelerate brain injury-associated neuroinflammation, neurodegeneration, and AD pathogenesis.
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Affiliation(s)
- Duraisamy Kempuraj
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs’, Columbia, MO 65201, USA
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Mohammad Ejaz Ahmed
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs’, Columbia, MO 65201, USA
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Govindhasamy Pushpavathi Selvakumar
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs’, Columbia, MO 65201, USA
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Ramasamy Thangavel
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs’, Columbia, MO 65201, USA
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Arshdeep S. Dhaliwal
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Iuliia Dubova
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs’, Columbia, MO 65201, USA
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Shireen Mentor
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Keerthivaas Premkumar
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Daniyal Saeed
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Haris Zahoor
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Sudhanshu P. Raikwar
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs’, Columbia, MO 65201, USA
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Smita Zaheer
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Shankar S. Iyer
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs’, Columbia, MO 65201, USA
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
| | - Asgar Zaheer
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs’, Columbia, MO 65201, USA
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO 65212, USA
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47
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Kery R, Chen APF, Kirschen GW. Genetic targeting of astrocytes to combat neurodegenerative disease. Neural Regen Res 2020; 15:199-211. [PMID: 31552885 PMCID: PMC6905329 DOI: 10.4103/1673-5374.265541] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Astrocytes, glial cells that interact extensively with neurons and other support cells throughout the central nervous system, have recently come under the spotlight for their potential contribution to, or potential regenerative role in a host of neurodegenerative disorders. It is becoming increasingly clear that astrocytes, in concert with microglial cells, activate intrinsic immunological pathways in the setting of neurodegenerative injury, although the direct and indirect consequences of such activation are still largely unknown. We review the current literature on the astrocyte’s role in several neurodegenerative diseases, as well as highlighting recent advances in genetic manipulation of astrocytes that may prove critical to modulating their response to neurological injury, potentially combatting neurodegenerative damage.
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Affiliation(s)
- Rachel Kery
- Medical Scientist Training Program (MSTP), Stony Brook Medicine; Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY, USA
| | - Allen P F Chen
- Medical Scientist Training Program (MSTP), Stony Brook Medicine; Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY, USA
| | - Gregory W Kirschen
- Medical Scientist Training Program (MSTP), Stony Brook Medicine, Stony Brook, NY, USA
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48
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Ramaswamy SB, Bhagavan SM, Kaur H, Giler GE, Kempuraj D, Thangavel R, Ahmed ME, Selvakumar GP, Raikwar SP, Zaheer S, Iyer SS, Govindarajan R, Zaheer A. Glia Maturation Factor in the Pathogenesis of Alzheimer's disease. OPEN ACCESS JOURNAL OF NEUROLOGY & NEUROSURGERY 2019; 12:79-82. [PMID: 32775957 PMCID: PMC7413177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative and neuroinflammatory disease characterized by the presence of extracellular amyloid plaques (APs) and intracellular neurofibrillary tangles (NFTs) in the brain. There is no disease modifying therapeutic options currently available for this disease. Hippocampus, entorhinal cortex (Broadmann area 28), perirhinal cortex (Broadmann area 35) and insular cortices are areas within the brain that are first ones to be severely affected in AD. Neuroinflammation is an important factor that induces neurodegeneration in AD. Glia maturation factor (GMF), a proinflammatory factor plays a crucial role in AD through activation of microglia and astrocytes to release proinflammatory mediators in the brain. Through immunohistochemical studies, we have previously shown that GMF is highly expressed in the vicinity of APs and NFTs in AD brains. Glial fibrillary acidic protein (GFAP), reactive astrocytes, ionized calcium binding adaptor molecule-1 (Iba-1) labelled activated microglia and GMF immunoreactive glial cells are increased in the entorhinal cortical layers especially at the sites of APs and Tau containing NFTs indicating a role for GMF. Overexpression of GMF in glial cells leads to neuroinflammation and neurodegeneration. Inhibition of GMF expression reduces neurodegeneration. Therefore, we suggest that GMF is a novel therapeutic target not only for AD but also for various other neurodegenerative diseases.
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Affiliation(s)
- Swathi Beladakere Ramaswamy
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Sachin M Bhagavan
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Harleen Kaur
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Gema E Giler
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Duraisamy Kempuraj
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Ramasamy Thangavel
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Mohammad Ejaz Ahmed
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Govindhasamy Pushpavathi Selvakumar
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Sudhanshu P. Raikwar
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Smita Zaheer
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Shankar S Iyer
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
| | - Raghav Govindarajan
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Asgar Zaheer
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA
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49
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Raikwar SP, Kikkeri NS, Sakuru R, Saeed D, Zahoor H, Premkumar K, Mentor S, Thangavel R, Dubova I, Ahmed ME, Selvakumar GP, Kempuraj D, Zaheer S, Iyer SS, Zaheer A. Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders. J Neuroimmune Pharmacol 2019; 14:608-641. [PMID: 31011884 PMCID: PMC8211357 DOI: 10.1007/s11481-019-09849-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 03/29/2019] [Indexed: 12/13/2022]
Abstract
Despite significant advancements in the field of molecular neurobiology especially neuroinflammation and neurodegeneration, the highly complex molecular mechanisms underlying neurodegenerative diseases remain elusive. As a result, the development of the next generation neurotherapeutics has experienced a considerable lag phase. Recent advancements in the field of genome editing offer a new template for dissecting the precise molecular pathways underlying the complex neurodegenerative disorders. We believe that the innovative genome and transcriptome editing strategies offer an excellent opportunity to decipher novel therapeutic targets, develop novel neurodegenerative disease models, develop neuroimaging modalities, develop next-generation diagnostics as well as develop patient-specific precision-targeted personalized therapies to effectively treat neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia etc. Here, we review the latest developments in the field of CRISPR-mediated genome editing and provide unbiased futuristic insights regarding its translational potential to improve the treatment outcomes and minimize financial burden. However, despite significant advancements, we would caution the scientific community that since the CRISPR field is still evolving, currently we do not know the full spectrum of CRISPR-mediated side effects. In the wake of the recent news regarding CRISPR-edited human babies being born in China, we urge the scientific community to maintain high scientific and ethical standards and utilize CRISPR for developing in vitro disease in a dish model, in vivo testing in nonhuman primates and lower vertebrates and for the development of neurotherapeutics for the currently incurable neurodegenerative disorders. Graphical Abstract.
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Affiliation(s)
- Sudhanshu P Raikwar
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
- U.S. Department of Veterans Affairs, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO, USA
| | - Nidhi S Kikkeri
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
| | - Ragha Sakuru
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
| | - Daniyal Saeed
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
| | - Haris Zahoor
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
| | - Keerthivaas Premkumar
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
| | - Shireen Mentor
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
- Department of Medical Biosciences, University of the Western Cape, Bellville, 7535, Republic of South Africa
| | - Ramasamy Thangavel
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
- U.S. Department of Veterans Affairs, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO, USA
| | - Iuliia Dubova
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
- U.S. Department of Veterans Affairs, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO, USA
| | - Mohammad Ejaz Ahmed
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
- U.S. Department of Veterans Affairs, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO, USA
| | - Govindhasamy P Selvakumar
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
- U.S. Department of Veterans Affairs, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO, USA
| | - Duraisamy Kempuraj
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
- U.S. Department of Veterans Affairs, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO, USA
| | - Smita Zaheer
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
| | - Shankar S Iyer
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA
- U.S. Department of Veterans Affairs, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO, USA
| | - Asgar Zaheer
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, 65211, USA.
- U.S. Department of Veterans Affairs, Harry S. Truman Memorial Veteran's Hospital, Columbia, MO, USA.
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50
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Kempuraj D, Selvakumar GP, Thangavel R, Ahmed ME, Zaheer S, Kumar KK, Yelam A, Kaur H, Dubova I, Raikwar SP, Iyer SS, Zaheer A. Glia Maturation Factor and Mast Cell-Dependent Expression of Inflammatory Mediators and Proteinase Activated Receptor-2 in Neuroinflammation. J Alzheimers Dis 2019; 66:1117-1129. [PMID: 30372685 DOI: 10.3233/jad-180786] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Parkinson's disease (PD) is characterized by the presence of inflammation-mediated dopaminergic neurodegeneration in the substantia nigra. Inflammatory mediators from activated microglia, astrocytes, neurons, T-cells and mast cells mediate neuroinflammation and neurodegeneration. Administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induces PD like motor deficits in rodents. 1-methyl-4-phenylpyridinium (MPP+), a toxic metabolite of MPTP activates glial cells, neurons and mast cells to release neuroinflammatory mediators. Glia maturation factor (GMF), mast cells and proteinase activated receptor-2 (PAR-2) are implicated in neuroinflammation. Alpha-synuclein which induces neurodegeneration increases PAR-2 expression in the brain. However, the exact mechanisms are not yet understood. In this study, we quantified inflammatory mediators in the brains of MPTP-administered wild type (Wt), GMF-knockout (GMF-KO), and mast cell knockout (MC-KO) mice. Additionally, we analyzed the effect of MPP+, GMF, and mast cell proteases on PAR-2 expression in astrocytes and neurons in vitro. Results show that the levels of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and the chemokine (C-C motif) ligand 2 (CCL2) were lesser in the brains of GMF-KO mice and MC-KO mice when compared to Wt mice brain after MPTP administration. Incubation of astrocytes and neurons with MPP+, GMF, and mouse mast cell protease-6 (MMCP-6) and MMCP-7 increased the expression of PAR-2. Our studies show that the absence of mast cells and GMF reduce the expression of neuroinflammatory mediators in the brain. We conclude that GMF along with mast cell interactions with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD and other neuroinflammatory disorders.
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Affiliation(s)
- Duraisamy Kempuraj
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.,Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Govindhasamy Pushpavathi Selvakumar
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.,Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Ramasamy Thangavel
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.,Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Mohammad Ejaz Ahmed
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.,Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Smita Zaheer
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Keerthana Kuppamma Kumar
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Anudeep Yelam
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Harleen Kaur
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Iuliia Dubova
- Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Sudhanshu P Raikwar
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.,Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Shankar S Iyer
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.,Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Asgar Zaheer
- Harry S. Truman Memorial Veterans Hospital, U.S. Department of Veterans Affairs, Columbia, MO, USA.,Department of Neurology, and the Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, MO, USA
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