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Gao J, Zhao D, Nouri HR, Chu HW, Huang H. Transcriptional Regulation of Mouse Mast Cell Differentiation and the Role of Human Lung Mast Cells in Airway Inflammation. Immunol Rev 2025; 331:e70026. [PMID: 40211768 PMCID: PMC12017346 DOI: 10.1111/imr.70026] [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: 09/16/2024] [Revised: 03/12/2025] [Accepted: 03/21/2025] [Indexed: 04/25/2025]
Abstract
Mast cells (MCs) play a critical role in allergic inflammation, anaphylaxis, and chronic inflammatory diseases such as asthma, COPD, and osteoarthritis. Dysregulated MC activation can lead to MC activation syndrome (MACS), which is observed in patients with long COVID. MCs express the high-affinity receptor for IgE and, upon activation, release mediators and cytokines that trigger anaphylactic shock and promote allergic inflammation. They also interact with epithelial and nerve cells, which are crucial in forming a complex network of cell-cell and gene-gene interactions driving chronic inflammation that can confer resistance to treatment. In this review, in the context of the literature, we focus on experiments conducted in our laboratory investigating how transcription factors and enhancers regulate genes critical in mouse MC differentiation and function related to human lung inflammation.
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Affiliation(s)
- Junfeng Gao
- Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Dianzheng Zhao
- Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Hamid Reza Nouri
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Hong Wei Chu
- Department of Medicine, National Jewish Health, Denver, CO 80206, USA
| | - Hua Huang
- Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206, USA
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Thomas SA, Lajoie S. Complement's involvement in allergic Th2 immunity: a cross-barrier perspective. J Clin Invest 2025; 135:e188352. [PMID: 40309766 PMCID: PMC12043088 DOI: 10.1172/jci188352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025] Open
Abstract
Type 2 (Th2) allergic diseases are chronic conditions characterized by a Th2-polarized immune response to allergens. These diseases can be categorized by affected barrier sites: skin (atopic dermatitis, allergic contact dermatitis), gut (food allergy), and respiratory tract (e.g., asthma, chronic rhinosinusitis). The global prevalence of Th2 allergic diseases has increased the need for a deeper understanding of their pathophysiology. Several associations have been identified between genetic variants in the genes encoding components of the complement system and allergic disease. Moreover, levels of several complement proteins are elevated in patients with allergy. Experimental evidence demonstrates that the complement system plays a critical role in the development of these diseases across barrier sites. While site-specific differences exist in the complement components involved, key pathways, particularly C3 and C5, are prominent across the skin, gut, and lung.
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Affiliation(s)
- Sarah A. Thomas
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Stephane Lajoie
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Charles N, Blank U. IgE-Mediated Activation of Mast Cells and Basophils in Health and Disease. Immunol Rev 2025; 331:e70024. [PMID: 40165512 DOI: 10.1111/imr.70024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 03/12/2025] [Indexed: 04/02/2025]
Abstract
Type 2-mediated immune responses protect the body against environmental threats at barrier surfaces, such as large parasites and environmental toxins, and facilitate the repair of inflammatory tissue damage. However, maladaptive responses to typically nonpathogenic substances, commonly known as allergens, can lead to the development of allergic diseases. Type 2 immunity involves a series of prototype TH2 cytokines (IL-4, IL-5, IL-13) and alarmins (IL-33, TSLP) that promote the generation of adaptive CD4+ helper Type 2 cells and humoral products such as allergen-specific IgE. Mast cells and basophils are integral players in this network, serving as primary effectors of IgE-mediated responses. These cells bind IgE via high-affinity IgE receptors (FcεRI) expressed on their surface and, upon activation by allergens, release a variety of mediators that regulate tissue responses, attract and modulate other inflammatory cells, and contribute to tissue repair. Here, we review the biology and effector mechanisms of these cells, focusing primarily on their role in mediating IgE responses in both physiological and pathological contexts.
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Affiliation(s)
- Nicolas Charles
- Université Paris Cité, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS EMR8252, Faculté de Médecine Site Bichat, Paris, France
- Laboratoire d'Excellence Inflamex, Université Paris Cité, Paris, France
| | - Ulrich Blank
- Université Paris Cité, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS EMR8252, Faculté de Médecine Site Bichat, Paris, France
- Laboratoire d'Excellence Inflamex, Université Paris Cité, Paris, France
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Mirazi H, Wood ST. Microfluidic chip-based co-culture system for modeling human joint inflammation in osteoarthritis research. Front Pharmacol 2025; 16:1579228. [PMID: 40271077 PMCID: PMC12015981 DOI: 10.3389/fphar.2025.1579228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 03/27/2025] [Indexed: 04/25/2025] Open
Abstract
Here we present a microfluidic model that allows for co-culture of human osteoblasts, chondrocytes, fibroblasts, and macrophages of both quiescent (M0) and pro-inflammatory (M1) phenotypes, maintaining initial viability of each cell type at 24 h of co-culture. We established healthy (M0-based) and diseased (M1-based) joint models within this system. An established disease model based on supplementation of IFN-γ and lipopolysaccharide in cell culture media was used to induce an M1 phenotype in macrophages to recapitulate inflammatory conditions found in Osteoarthritis. Cell viability was assessed using NucBlue™ Live and NucGreen™ Dead fluorescent stains, with mean viability of 83.9% ± 14% and 83.3% ± 12% for healthy and diseased models, respectively, compared with 93.3% ± 4% for cell in standard monoculture conditions. Cytotoxicity was assessed via a lactate dehydrogenase (LDH) assay and showed no measurable increase in lactate dehydrogenase release into the culture medium under co-culture conditions, indicating that neither model promotes a loss of cell membrane integrity due to cytotoxic effects. Cellular metabolic activity was assessed using a PrestoBlue™ assay and indicated increased cellular metabolic activity in co-culture, with levels 5.9 ± 3.2 times mean monolayer cell metabolic activity levels in the healthy joint model and 5.3 ± 3.4 times mean monolayer levels in the diseased model. Overall, these findings indicate that the multi-tissue nature of in vivo human joint conditions can be recapitulated by our microfluidic co-culture system at 24 h and thus this model serves as a promising tool for studying the pathophysiology of rheumatic diseases and testing potential therapeutics.
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Affiliation(s)
- Hosein Mirazi
- Department of Nanoscience and Biomedical Engineering, South Dakota School of Mines and Technology, Rapid City, SD, United States
| | - Scott T. Wood
- Department of Nanoscience and Biomedical Engineering, South Dakota School of Mines and Technology, Rapid City, SD, United States
- Portland Laboratory for Biotechnology and Health Sciences, University of New England, Portland, ME, United States
- Department of Biomedical Sciences, University of New England, Biddeford, ME, United States
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Molfetta R, Carnevale A, Marangio C, Putro E, Paolini R. Beyond the "Master" Role in Allergy: Insights into Intestinal Mast Cell Plasticity and Gastrointestinal Diseases. Biomedicines 2025; 13:320. [PMID: 40002733 PMCID: PMC11853218 DOI: 10.3390/biomedicines13020320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/10/2025] [Accepted: 01/27/2025] [Indexed: 02/27/2025] Open
Abstract
Mast cells (MCs) are essential components of the immune system that enter the circulation as immature bone marrow progenitors and differentiate in peripheral organs under the influence of microenvironment factors. As tissue-resident secretory immune cells, MCs rapidly detect the presence of bacteria and parasites because they harbor many surface receptors, which enable their activation via a multitude of stimuli. MC activation has been traditionally linked to IgE-mediated allergic reactions, but MCs play a pivotal role in different physiological and pathological processes. In gut, MCs are essential for the maintenance of gastrointestinal (GI) barrier function, and their interactions with neurons, immune cells, and epithelial cells have been related to various GI disorders. This review recapitulates intestinal MC roles in diseases with a main focus on inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Emerging therapies targeting MCs and their mediators in clinical practices will also be discussed.
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Affiliation(s)
| | | | | | | | - Rossella Paolini
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy; (R.M.); (A.C.); (C.M.); (E.P.)
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Song X, Jiao J, Qin J, Zhang W, Qin W, Ma S. Single-cell transcriptomics reveals the heterogeneity and function of mast cells in human ccRCC. Front Immunol 2025; 15:1494025. [PMID: 39840068 PMCID: PMC11747552 DOI: 10.3389/fimmu.2024.1494025] [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: 09/10/2024] [Accepted: 12/12/2024] [Indexed: 01/23/2025] Open
Abstract
Introduction The role of mast cells (MCs) in clear cell renal carcinoma (ccRCC) is unclear, and comprehensive single-cell studies of ccRCC MCs have not yet been performed. Methods To investigate the heterogeneity and effects of MCs in ccRCC, we studied single-cell transcriptomes from four ccRCC patients, integrating both single-cell sequencing and bulk tissue sequencing data from online sequencing databases, followed by validation via spatial transcriptomics and multiplex immunohistochemistry (mIHC). Results We identified four MC signature genes (TPSB2, TPSAB1, CPA3, and HPGDS). MC density was significantly greater in ccRCC tissues than in normal tissues, but MC activation characteristics were not significantly different between ccRCC and normal tissues. Activated and resting MCs were defined as having high and low expression of MC receptors and mediators, respectively, whereas proliferating MCs had high expression of proliferation-related genes. The overall percentage of activated MCs in ccRCC tissues did not change significantly but shifted toward a more activated subpopulation (VEGFA+ MCs), with a concomitant decrease in proliferative MCs (TNF+ MCs) and resting MCs. An analysis of the ratio of TNF+/VEGFA+ MCs in tumors revealed that MCs exerted antitumor effects on ccRCC. However, VEGFA+MC was produced in large quantities in ccRCC tissues and promoted tumor angiogenesis compared with adjacent normal tissues, which aroused our concern. In addition, MC signature genes were associated with a better prognosis in the KIRC patient cohort in the TCGA database, which is consistent with our findings. Furthermore, the highest level of IL1B expression was observed in macrophages in ccRCC samples, and spatial transcriptome analysis revealed the colocalization of VEGFA+ MCs with IL1B+ macrophages at the tumor-normal interface. Discussion In conclusion, this study revealed increased MC density in ccRCC. Although the proportion of activated MCs was not significantly altered in ccRCC tissues compared with normal tissues, this finding highlights a shift in the MC phenotype from CTSGhighMCs to more activated VEGFA+MCs, providing a potential therapeutic target for inhibiting ccRCC progression.
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Affiliation(s)
- Xiyu Song
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi’an, Shaanxi, China
- Xijing Innovation Research Institute, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jianhua Jiao
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- Xijing Innovation Research Institute, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jiayang Qin
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Zhang
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- Xijing Innovation Research Institute, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Shuaijun Ma
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- Xijing Innovation Research Institute, Fourth Military Medical University, Xi’an, Shaanxi, China
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Hao G, Han S, Xiao Z, Shen J, Zhao Y, Hao Q. Synovial mast cells and osteoarthritis: Current understandings and future perspectives. Heliyon 2024; 10:e41003. [PMID: 39720069 PMCID: PMC11665477 DOI: 10.1016/j.heliyon.2024.e41003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 10/29/2024] [Accepted: 12/04/2024] [Indexed: 12/26/2024] Open
Abstract
Osteoarthritis (OA) is a prevalent joint disease worldwide that significantly impacts the quality of life of individuals, particularly those in middle-aged and elderly populations. OA was initially considered as non-inflammatory arthritis, but recent studies have identified a substantial number of immune responses in OA, leading to the recognition of inflammation as a key factor in its pathogenesis. An increasing number of studies have found that mast cell (MC) and MC-secreted inflammatory mediators and cytokines are notably increased in the synovial fluid of OA patients, indicating a potential association between MCs and the onset and progression of synovial inflammation. The present review aims to summarize the significance and mechanism of MCs in the pathogenesis of OA. Meanwhile, we also discuss the clinical potential of using MCs as therapeutic target for OA therapy. Modulating the activities of MCs or the mediators of MCs in the synovial fluid inflammatory microenvironment will be promising new options for the treatment of OA.
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Affiliation(s)
- Guanghui Hao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Shanqian Han
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Qi Hao
- Department of Joint Surgery, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
- The Third People's Hospital of Longmatan District, Luzhou, Sichuan, China
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Guo TZ, Shi X, Li X, Li WW, Wei T, Sahbaie P, McAllister TN, Angst MS, Clark JD, Kingery WS. Autoantibodies cause nociceptive sensitization in a mouse model of degenerative osteoarthritis. Pain 2024:00006396-990000000-00794. [PMID: 39835597 DOI: 10.1097/j.pain.0000000000003500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 10/24/2024] [Indexed: 01/22/2025]
Abstract
ABSTRACT Previous preclinical and translational studies suggest that tissue trauma related to bony fracture and intervertebral disk disruption initiates the formation of pronociceptive antibodies that support chronic musculoskeletal pain conditions. This study tested this hypothesis in the monosodium iodoacetate (MIA) mouse model of osteoarthritis (OA) and extended the findings using OA patient samples. Monosodium iodoacetate was injected unilaterally into the knees of male and female wild-type (WT) and muMT mice (lacking B cells) to induce articular cartilage damage. Repeated nociceptive behavioral testing was performed, and serum was collected for antibody isolation and passive transfer experiments. Serum antibodies collected from patients with OA were tested in MIA-treated muMT mice. Biochemical analyses were performed on knee joint tissues. Monosodium iodoacetate-treated WT mice developed chronic ipsilateral hindlimb allodynia, hyperalgesia, and unweighting, but these pain behaviors were absent in MIA-treated muMT mice, indicating that cartilage injury-induced pain is B-cell dependent. IgM accumulation was observed in the knee tissues of MIA-treated mice, and intra-articular injection of IgM from MIA-treated mice into MIA-treated muMT mice caused nociceptive sensitization. Similarly, intra-articular injection of IgM from patients with OA was pronociceptive in muMT MIA mice and control subject IgM had no effect. Monosodium iodoacetate-injected joints demonstrate elevated levels of complement component 5a (C5a) and C5a receptor blockade using intra-articular PMX-53-reduced sensitization. These data suggest that MIA-treated mice and patients with OA generate pronociceptive antibodies, and further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain.
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Affiliation(s)
- Tian-Zhi Guo
- Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
| | - Xiaoyou Shi
- Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
- Department of Anesthesiology Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Xuanying Li
- Department of Anesthesiology Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Wen-Wu Li
- Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
- Department of Anesthesiology Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Tzuping Wei
- Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
| | - Peyman Sahbaie
- Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
- Department of Anesthesiology Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Tiffany N McAllister
- Department of Anesthesiology Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Martin S Angst
- Department of Anesthesiology Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - J David Clark
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
- Department of Anesthesiology Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Wade S Kingery
- Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States
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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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10
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Sutradhar S, Ali H. Mast cell MrgprB2 in neuroimmune interaction in IgE-mediated airway inflammation and its modulation by β-arrestin2. Front Immunol 2024; 15:1470016. [PMID: 39483467 PMCID: PMC11524863 DOI: 10.3389/fimmu.2024.1470016] [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: 07/24/2024] [Accepted: 09/25/2024] [Indexed: 11/03/2024] Open
Abstract
Introduction Allergic asthma has been linked to the activation of mast cells (MCs) by the neuropeptide substance P (SP), but the mechanism underlying this neuroimmune interaction is unknown. Substance P produced from cutaneous nociceptors activates MCs via Mas-related G-protein-coupled receptor B2 (MrgprB2) to enhance type 2 immune response in experimental atopic dermatitis in mice. We recently showed that the adapter protein β-arrestin2 (β-arr2) contributes to MrgprB2-mediated MC chemotaxis. The goals of this study were to determine if MrgprB2 facilitates neuroimmune interaction in IgE (FcεRI)-mediated allergic airway inflammation (AAI) and to assess if this response is modulated by β-arr2. Methods Wild-type (WT), MrgprB2-/- mice and mice with MC-specific deletion of β-arr2 (Cpa3Cre+ /β-arr2fl/fl ) were passively sensitized with anti-TNP-IgE and challenged with antigen. The generation of SP and MC recruitment in the lung were determined by immunofluorescence and toluidine blue staining, respectively. The transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokines in lung tissue were assessed by RT-PCR, and the release of selected cytokines in bronchoalveolar lavage (BAL) was determined by ELISA. Eosinophil and neutrophil recruitment in lung tissue and BAL were determined by immunofluorescence staining and flow cytometry, respectively. Goblet cell hyperplasia was determined by periodic acid-Schiff staining. Results Following IgE sensitization and antigen challenge in WT mice, SP generation, and MC recruitment, transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokine were upregulated when compared to the control challenge. TNF-α, Th2 cytokine production, eosinophil/neutrophil recruitment, and goblet cell hyperplasia were also increased. These responses were significantly reduced in MrgprB2-/- and Cpa3Cre+ /β-arr2fl/fl mice. Discussion The data presented herein suggest that SP-mediated MrgprB2 activation contributes to AAI and goblet cell hyperplasia in mice. Furthermore, these responses are modulated by β-arr2, which promotes MC recruitment to facilitate their activation through FcεRI.
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Affiliation(s)
| | - Hydar Ali
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Gao H, Nepovimova E, Adam V, Heger Z, Valko M, Wu Q, Kuca K. Age-associated changes in innate and adaptive immunity: role of the gut microbiota. Front Immunol 2024; 15:1421062. [PMID: 39351234 PMCID: PMC11439693 DOI: 10.3389/fimmu.2024.1421062] [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: 04/21/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Aging is generally regarded as an irreversible process, and its intricate relationship with the immune system has garnered significant attention due to its profound implications for the health and well-being of the aging population. As people age, a multitude of alterations occur within the immune system, affecting both innate and adaptive immunity. In the realm of innate immunity, aging brings about changes in the number and function of various immune cells, including neutrophils, monocytes, and macrophages. Additionally, certain immune pathways, like the cGAS-STING, become activated. These alterations can potentially result in telomere damage, the disruption of cytokine signaling, and impaired recognition of pathogens. The adaptive immune system, too, undergoes a myriad of changes as age advances. These include shifts in the number, frequency, subtype, and function of T cells and B cells. Furthermore, the human gut microbiota undergoes dynamic changes as a part of the aging process. Notably, the interplay between immune changes and gut microbiota highlights the gut's role in modulating immune responses and maintaining immune homeostasis. The gut microbiota of centenarians exhibits characteristics akin to those found in young individuals, setting it apart from the microbiota observed in typical elderly individuals. This review delves into the current understanding of how aging impacts the immune system and suggests potential strategies for reversing aging through interventions in immune factors.
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Affiliation(s)
- Haoyu Gao
- College of Life Science, Yangtze University, Jingzhou, China
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, Czechia
| | - Vojtech Adam
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czechia
| | - Zbynek Heger
- Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czechia
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, Slovakia
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou, China
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, Czechia
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, Czechia
- Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI), University of Granada, Granada, Spain
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12
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Ertuğrul T, Tütüncü Ş, Delice N, Özdemir B. Histochemical and immunohistochemical investigation of the number and localization of mast cells in the feline tongue. Anat Histol Embryol 2024; 53:e13069. [PMID: 38831730 DOI: 10.1111/ahe.13069] [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: 02/01/2023] [Revised: 05/17/2024] [Accepted: 05/27/2024] [Indexed: 06/05/2024]
Abstract
This is the first study to describe the subtypes, number and distribution of mast cells (MC) in cat tongue by histochemical and immunohistochemical methods. Six male adult felines' tongue tissue samples consist of the study's material. Samples were fixed in 10% formaldehyde. MC number and distribution in the feline tongue were assessed using toluidine blue. Also, sections taken from blocks were stained in alcian blue/safranin O (AB/SO) combined dyes to determine the MC subtypes. The Streptavidin biotin complex method using anti-chymase and anti-tryptase primary antibodies was used for immunohistochemistry. Metachromatic MCs were mainly observed in the lamina propria close to the multilayered keratinized stratified squamous epithelium. The high number of MCs in this region may be because the dorsal surface of the tongue plays an essential role in the defence system of tongue tissue and, thus, of the body as a whole. Additionally, the number of MCs stained with AB (+) (1.7 ± 0.08) in the feline tongue was statistically higher than those with SO (+) (0.18 ± 0.02). This might be interpreted as an indication that MC heterogeneity may be due not only to their staining properties but also to their localization. It is also conceivable that the high histamine content may be a factor in this. Tryptase-positive MCs were found in the loose connective tissue around blood vessels, between the glands, as solitary cells, or in groups of several cells. Chymase-positive MCs were observed more individually rather than in groups. Moreover, chymase-positive MCs were detected to be located in the filiform papillae subepithelial and in the blood vessels' immediate vicinity. Animals often lick themselves to clean themselves and promote healing. For this reason, it is very important to protect the tongue, which is in direct contact with the external environment, against foreign agents. Considering both the functional and protective properties of the tongue, we concluded that MCs may play a role in oral cavity immunity and protective effect.
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Affiliation(s)
- Tuğrul Ertuğrul
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Şerife Tütüncü
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Nurcan Delice
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - Bengül Özdemir
- Department of Histology and Embryology, Faculty of Medicine, Kafkas University, Kars, Turkey
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13
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Htoo A, Qualia CM, George R, Arker SH, Subasi NB, Lee H, Chung L, Chen A. Expression of CD25, mast cell markers and T-cell markers in eosinophilic esophagitis. Ann Diagn Pathol 2024; 70:152287. [PMID: 38479198 DOI: 10.1016/j.anndiagpath.2024.152287] [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: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 04/30/2024]
Abstract
While eosinophilic esophagitis (EOE) is defined by histologic presence of eosinophils, a few studies have established the presence of mast cells in EOE and even shown their correlation with symptom persistence despite resolution of eosinophils. Expression of aberrant mast cell markers CD25 and CD2 have not been studied in EOE. This study quantifies the number of hotspot cells per high power field expressing CKIT/CD117, tryptase, CD25, CD2 and CD3 by immunohistochemical stains in endoscopic esophageal biopsies of the following three cohorts: (1) established and histologically confirmed EOE, (2) suspected EOE with biopsies negative for eosinophils, and (3) no history of or suspicion for EOE with histologically unremarkable biopsies. In this study, mast cells were highlighted by CKIT and tryptase in EOE, and not seen in other clinically mimicking cases. There were also significantly higher densities of CD25 and pan-T-cell marker staining in EOE cases. These findings suggest an inflammatory cellular milieu in EOE, beyond just eosinophils, that can be demonstrated by immunohistochemistry, and that invite further study into the role that these cells may play in EOE.
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Affiliation(s)
- Arkar Htoo
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | - Cary M Qualia
- Department of Pediatrics, Albany Medical Center, Albany, NY, USA
| | - Rose George
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | - Soe Htet Arker
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | | | - Hwajeong Lee
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | - Lorene Chung
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | - Anne Chen
- Department of Pathology, Albany Medical Center, Albany, NY, USA; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.
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14
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Gong Y, Johnsson AK, Säfholm J, Al-Ameri M, Sachs E, Vali K, Nilsson G, Rönnberg E. An optimized method for IgE-mediated degranulation of human lung mast cells. Front Immunol 2024; 15:1393802. [PMID: 38881896 PMCID: PMC11179429 DOI: 10.3389/fimmu.2024.1393802] [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: 02/29/2024] [Accepted: 05/10/2024] [Indexed: 06/18/2024] Open
Abstract
Background Mast cells are critically involved in IgE-mediated diseases, e.g., allergies and asthma. Human mast cells are heterogeneous, and mast cells from different anatomical sites have been shown to respond differently to certain stimuli and drugs. The origin of the mast cells is therefore of importance when setting up a model system, and human lung mast cells are highly relevant cells to study in the context of asthma. We therefore set out to optimize a protocol of IgE-mediated activation of human lung mast cells. Methods Human lung mast cells were extracted from lung tissue obtained from patients undergoing pulmonary resection by enzyme digestion and mechanical disruption followed by CD117 magnetic-activated cell sorting (MACS) enrichment. Different culturing media and conditions for the IgE-mediated degranulation were tested to obtain an optimized method. Results IgE crosslinking of human lung mast cells cultured in serum-free media gave a stronger response compared to cells cultured with 10% serum. The addition of stem cell factor (SCF) did not enhance the degranulation. However, when the cells were put in fresh serum-free media 30 minutes prior to the addition of anti-IgE antibodies, the cells responded more vigorously. Maximum degranulation was reached 10 minutes after the addition of anti-IgE. Both CD63 and CD164 were identified as stable markers for the detection of degranulated mast cells over time, while the staining with anti-CD107a and avidin started to decline 10 minutes after activation. The levels of CD203c and CD13 did not change in activated cells and therefore cannot be used as degranulation markers of human lung mast cells. Conclusions For an optimal degranulation response, human lung mast cells should be cultured and activated in serum-free media. With this method, a very strong and consistent degranulation response with a low donor-to-donor variation is obtained. Therefore, this model is useful for further investigations of IgE-mediated mast cell activation and exploring drugs that target human lung mast cells, for instance, in the context of asthma.
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Affiliation(s)
- Yitao Gong
- Division of Immunology and Allergy, Department of Medicine Solna, and Center for Molecular Medicine, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
| | - Anna-Karin Johnsson
- Division of Immunology and Allergy, Department of Medicine Solna, and Center for Molecular Medicine, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
| | - Jesper Säfholm
- Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden
| | - Mamdoh Al-Ameri
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Cardiothoracic Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Erik Sachs
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Cardiothoracic Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Kasra Vali
- Department of Cardiothoracic Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Gunnar Nilsson
- Division of Immunology and Allergy, Department of Medicine Solna, and Center for Molecular Medicine, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Elin Rönnberg
- Division of Immunology and Allergy, Department of Medicine Solna, and Center for Molecular Medicine, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
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15
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Putro E, Carnevale A, Marangio C, Fulci V, Paolini R, Molfetta R. New Insight into Intestinal Mast Cells Revealed by Single-Cell RNA Sequencing. Int J Mol Sci 2024; 25:5594. [PMID: 38891782 PMCID: PMC11171657 DOI: 10.3390/ijms25115594] [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: 04/04/2024] [Revised: 05/14/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
Mast cells (MCs) are tissue-resident immune cells distributed in all tissues and strategically located close to blood and lymphatic vessels and nerves. Thanks to the expression of a wide array of receptors, MCs act as tissue sentinels, able to detect the presence of bacteria and parasites and to respond to different environmental stimuli. MCs originate from bone marrow (BM) progenitors that enter the circulation and mature in peripheral organs under the influence of microenvironment factors, thus differentiating into heterogeneous tissue-specific subsets. Even though MC activation has been traditionally linked to IgE-mediated allergic reactions, a role for these cells in other pathological conditions including tumor progression has recently emerged. However, several aspects of MC biology remain to be clarified. The advent of single-cell RNA sequencing platforms has provided the opportunity to understand MCs' origin and differentiation as well as their phenotype and functions within different tissues, including the gut. This review recapitulates how single-cell transcriptomic studies provided insight into MC development as well as into the functional role of intestinal MC subsets in health and disease.
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Affiliation(s)
| | | | | | | | - Rossella Paolini
- Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy; (E.P.); (A.C.); (C.M.); (V.F.); (R.M.)
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16
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Ribatti D, Dammacco R. Mast cells in human choroid and their role in age-related macular degeneration (AMD). Clin Exp Med 2024; 24:98. [PMID: 38727918 PMCID: PMC11087330 DOI: 10.1007/s10238-024-01361-9] [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: 03/25/2024] [Accepted: 04/28/2024] [Indexed: 05/13/2024]
Abstract
The role of mast cells in physiologic and pathological processes extends far beyond the allergy processes: they are involved in wound healing, chronic inflammation, and tumor growth. This short article emphasizes the role played by mast cells in age-related macular degeneration (AMD). Mast cells can induce angiogenesis and are present around Bruch's membrane during the early and late stages of choroidal neovascularization in AMD. Proteolytic enzymes released by mast cells lead to thinning of the choroid in AMD as well as degradation of vascular basement membranes and Bruch's membrane, which in turn could result in retinal pigment epithelial death and choriocapillaris degeneration in geographical atrophy and exudative AMD.
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Affiliation(s)
- Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy.
| | - Rosanna Dammacco
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy
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17
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Kim HY, Jeong KM, Kim SH, Choi YJ, Kang HG, Jung H, Min K, Kim HM, Jeong HJ. Modulating effect of Eunkyo-san on expression of inflammatory cytokines and angiotensin-converting enzyme 2 in human mast cells. In Vitro Cell Dev Biol Anim 2024; 60:195-208. [PMID: 38228999 DOI: 10.1007/s11626-024-00847-w] [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: 08/16/2023] [Accepted: 12/19/2023] [Indexed: 01/18/2024]
Abstract
Eunkyo-san is widely used in the treatment of severe respiratory infections. Mast cells not only serve as host cells for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but also they also exacerbate Coronavirus disease in 2019 (COVID-19) by causing a cytokine storm. Here we investigated whether Eunkyo-san and its active compound naringenin regulate the expression of inflammatory cytokines and factors connected to viral infection in activated human mast cell line, HMC-1 cells. Eunkyo-san and naringenin significantly reduced levels of inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-8, thymic stromal lymphopoietin, and tumor necrosis factor-α without impacting cytotoxicity. Eunkyo-san and naringenin reduced levels of factors connected to SARS-CoV-2 infection such as angiotensin-converting enzyme 2 (ACE2, SARS-CoV-2 receptor), transmembrane protease/serine subfamily member 2, and tryptase in activated HMC-1 cells. Treatment with Eunkyo-san and naringenin considerably reduced expression levels of ACE2 transcription factor, AP-1 (C-JUN and C-FOS) by blocking phosphatidylinositide-3-kinase and c-Jun NH2-terminal kinases signaling pathways. In addition, Eunkyo-san and naringenin effectively suppressed activation of signal transducer and activator of transcription 3, nuclear translocation of nuclear factor-κB, and activation of caspase-1 in activated HMC-1 cells. Furthermore, Eunkyo-san and naringenin reduced expression of ACE2 mRNA in two activated mast cell lines, RBL-2H3 and IC-2 cells. The overall study findings showed that Eunkyo-san diminished the expression levels of inflammatory cytokines and ACE2, and these findings imply that Eunkyo-san is able to effectively mitigating the cytokine storm brought on by SARS-CoV-2 infection.
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Affiliation(s)
- Hee-Yun Kim
- Biochip Research Center, Hoseo University, Asan, 31499, Republic of Korea
| | - Kyung-Min Jeong
- Division of Food and Pharmaceutical Engineering, Hoseo University, Asan, 31499, Republic of Korea
| | - Seung-Hwan Kim
- Division of Food and Pharmaceutical Engineering, Hoseo University, Asan, 31499, Republic of Korea
| | - Yu-Jin Choi
- Division of Food and Pharmaceutical Engineering, Hoseo University, Asan, 31499, Republic of Korea
| | - Ho-Geun Kang
- Department of Bio-Convergence System, Graduate School, Hoseo University, Asan, 31499, Republic of Korea
| | - Hanchul Jung
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Kyunghwon Min
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Hyung-Min Kim
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
| | - Hyun-Ja Jeong
- Biochip Research Center, Hoseo University, Asan, 31499, Republic of Korea.
- Division of Food and Pharmaceutical Engineering, Hoseo University, Asan, 31499, Republic of Korea.
- Department of Bio-Convergence System, Graduate School, Hoseo University, Asan, 31499, Republic of Korea.
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18
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Kovacheva E, Gevezova M, Maes M, Sarafian V. Mast Cells in Autism Spectrum Disorder-The Enigma to Be Solved? Int J Mol Sci 2024; 25:2651. [PMID: 38473898 DOI: 10.3390/ijms25052651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Autism Spectrum Disorder (ASD) is a disturbance of neurodevelopment with a complicated pathogenesis and unidentified etiology. Many children with ASD have a history of "allergic symptoms", often in the absence of mast cell (MC)-positive tests. Activation of MCs by various stimuli may release molecules related to inflammation and neurotoxicity, contributing to the development of ASD. The aim of the present paper is to enrich the current knowledge on the relationship between MCs and ASD by discussing key molecules and immune pathways associated with MCs in the pathogenesis of autism. Cytokines, essential marker molecules for MC degranulation and therapeutic targets, are also highlighted. Understanding the relationship between ASD and the activation of MCs, as well as the involved molecules and interactions, are the main points contributing to solving the enigma. Key molecules, associated with MCs, may provide new insights to the discovery of drug targets for modeling inflammation in ASD.
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Affiliation(s)
- Eleonora Kovacheva
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Maria Gevezova
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Michael Maes
- Research Institute, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
- Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, China
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Cognitive Fitness and Technology Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Department of Psychiatry, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
| | - Victoria Sarafian
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
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19
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Genta RM, Turner KO, Collins MH, Wechsler JB, Arva NC, Pletneva MA, Dellon ES, Walker MM. Quantification of Mucosal Mast Cells in the Gastrointestinal Tract: A Primer for Practicing Pathologists. Arch Pathol Lab Med 2024; 148:e25-e35. [PMID: 37450346 DOI: 10.5858/arpa.2023-0070-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2023] [Indexed: 07/18/2023]
Abstract
CONTEXT.— Mast cells are essential components of the immune system and play crucial pathogenetic roles in several digestive diseases, including mastocytic enterocolitis and eosinophilic gastrointestinal disorders. Pathologists have rarely been asked to evaluate the distribution and density of mast cells in gastrointestinal (GI) biopsy specimens. However, such requests are becoming more common because of an increasing awareness of the role of mast cells in functional GI disease and in both esophageal and nonesophageal eosinophilic gastrointestinal disorders. OBJECTIVE.— To provide pathologists with tools to incorporate the assessment of mast cells in the evaluation of esophageal, gastric, and intestinal specimens by developing a systematic approach to their evaluation, counting, and reporting. DESIGN.— This study consisted of a review of the literature followed by multiple consensus sessions to decide where to count mast cells and what a countable mast cell is. RESULTS.— We reviewed 135 papers addressing the content of mast cells in the digestive tract, selected 21 that detailed how cells were counted (microscope lens, area of high-power fields, locations evaluated, type of cells considered as countable), and summarized their data in a table. Then, drawing from both the acceptable literature and our own extensive experience, we reached a tentative consensus on: (1) the normal numbers in the different segments of the GI tract; (2) the morphology of countable mast cells; and (3) the locations and strategies for counting them. CONCLUSIONS.— The result is a set of suggestions for reporting mast cell counts, their distribution, and their location in a way clinicians can understand and use for management decisions.
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Affiliation(s)
- Robert M Genta
- From the Departments of Pathology and Medicine (Gastroenterology), Baylor College of Medicine, Houston, Texas (Genta)
- Inform Diagnostics, Fulgent, Irving, Texas (Genta, Turner)
| | - Kevin O Turner
- Inform Diagnostics, Fulgent, Irving, Texas (Genta, Turner)
- the Department of Pathology, University of Minnesota Medical School, Minneapolis (Turner)
| | - Margaret H Collins
- the Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio (Collins)
| | - Joshua B Wechsler
- the Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Departments of Pediatrics (Wechsler) and Pathology (Arva), Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Nicoleta C Arva
- the Eosinophilic Gastrointestinal Diseases Program, Division of Gastroenterology, Hepatology, and Nutrition, Departments of Pediatrics (Wechsler) and Pathology (Arva), Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
| | - Maria A Pletneva
- the Department of Pathology, University of Utah, Salt Lake City (Pletneva)
| | - Evan S Dellon
- the Center for Esophageal Diseases and Swallowing (Dellon)
- the Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine (Dellon), University of North Carolina School of Medicine, Chapel Hill
| | - Marjorie M Walker
- Anatomical Pathology, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia (Walker)
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20
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Praetzel R, Motaghed M, Fereydouni M, Ahani E, Kepley C. Description and Characterization of Three-Dimensional Human Mast Cell Progenitor Spheroids In Vitro. Cureus 2024; 16:e53708. [PMID: 38455803 PMCID: PMC10919245 DOI: 10.7759/cureus.53708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/28/2024] [Indexed: 03/09/2024] Open
Abstract
Human mast cells (MC) are an essential component of the immune system as they uniquely store and release a wide range of soluble mediators through IgE and non-IgE mechanisms. Several tissue sources can be used to differentiate functional MC for in vitro and in vivo studies. Here we describe an improved method for obtaining large numbers of human MC from adipose tissue with advantages over current methods. We analyzed donor parameters (e.g. age, race) on MC-isolation following adipose and skin tissue digestion from healthy donors. Adipose and skin-derived MC were morphologically and immunophenotypically similar in all donors regardless of age. However, donor-dependent variations in MC numbers were observed following tissue digestion. In addition, we identified and characterized three-dimensional structures from which mature MC emerged in vitro using peripheral blood and human tissue sources. MC progenitor spheroids (MCPS) appeared approximately one week following progenitor isolation and were consistently observed to have mature MC attached, emerging, or nearby when cultured in a stem cell factor-containing medium. The overall characteristics of the MCPS were similar from each tissue source. We propose that these MCPS serve as the common source of human MC in vitro.
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Affiliation(s)
- Rebecca Praetzel
- Department of Molecular and Cellular Sciences, Liberty University College of Osteopathic Medicine, Lynchburg, USA
| | - Mona Motaghed
- Department of Nanoengineering, North Carolina Agricultural and Technical State University, Greensboro, USA
| | - Mohammad Fereydouni
- Department of Nanoscience, University of North Carolina at Greensboro, Greensboro, USA
| | - Elnaz Ahani
- Department of Nanoengineering, North Carolina Agricultural and Technical State University, Greensboro, USA
| | - Chris Kepley
- Department of Molecular and Cellular Sciences, Liberty University College of Osteopathic Medicine, Lynchburg, USA
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21
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Zmorzynski S, Kimicka-Szajwaj A, Szajwaj A, Czerwik-Marcinkowska J, Wojcierowski J. Genetic Changes in Mastocytes and Their Significance in Mast Cell Tumor Prognosis and Treatment. Genes (Basel) 2024; 15:137. [PMID: 38275618 PMCID: PMC10815783 DOI: 10.3390/genes15010137] [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: 12/14/2023] [Revised: 01/12/2024] [Accepted: 01/20/2024] [Indexed: 01/27/2024] Open
Abstract
Mast cell tumors are a large group of diseases occurring in dogs, cats, mice, as well as in humans. Systemic mastocytosis (SM) is a disease involving the accumulation of mast cells in organs. KIT gene mutations are very often seen in abnormal mast cells. In SM, high KIT/CD117 expression is observed; however, there are usually no KIT gene mutations present. Mastocytoma (MCT)-a form of cutaneous neoplasm-is common in animals but quite rare in humans. KIT/CD117 receptor mutations were studied as the typical changes for human mastocytosis. In 80% of human cases, the KIT gene substitution p.D816H was present. In about 25% of MCTs, metastasis was observed. Changes in the gene expression of certain genes, such as overexpression of the DNAJ3A3 gene, promote metastasis. In contrast, the SNORD93 gene blocks the expression of metastasis genes. The panel of miR-21-5p, miR-379, and miR-885 has a good efficiency in discriminating healthy and MCT-affected dogs, as well as MCT-affected dogs with and without nodal metastasis. Further studies on the pathobiology of mast cells can lead to clinical improvements, such as better MCT diagnosis and treatment. Our paper reviews studies on the topic of mast cells, which have been carried out over the past few years.
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Ribatti D. Mast cells are at the interface between the external environment and the inner organism. Front Med (Lausanne) 2024; 10:1332047. [PMID: 38239615 PMCID: PMC10794488 DOI: 10.3389/fmed.2023.1332047] [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: 11/02/2023] [Accepted: 11/30/2023] [Indexed: 01/22/2024] Open
Abstract
Mast cells localized at the level of the mucosal barrier in the skin, lung, and gastrointestinal tract, intervene in the modulation of the function of the epithelial cells and are involved in innate and adaptive defensive responses. In this context, mast cells intervene in the recognition and clearance of microbial pathogens. This mini-review article discusses the role of mast cells in these barrier systems.
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Affiliation(s)
- Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy
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23
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Alda S, Ceausu RA, Gaje PN, Raica M, Cosoroaba RM. Mast Cell: A Mysterious Character in Skin Cancer. In Vivo 2024; 38:58-68. [PMID: 38148067 PMCID: PMC10756458 DOI: 10.21873/invivo.13410] [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: 07/24/2023] [Revised: 09/17/2023] [Accepted: 09/25/2023] [Indexed: 12/28/2023]
Abstract
Cutaneous malignancies represent a real concern and burden for the healthcare system, not only due to their increased frequency, but also due to the significant number of deaths attributed to these types of cancer. The genesis of tumors, their progression and metastasis are highly complex and researched subjects; apparently, mast cells (MCs) constitute an important piece in the complicated jigsaw puzzle of cancer. This article reviews the current knowledge of the roles MCs might play in the development of cutaneous malignancies. Besides their well-known and studied role in allergic reactions, MCs are linked to multiple and various disorders, including cancer. MCs exhibit incredible heterogeneity, being able to secrete numerous mediators that influence the tumor microenvironment and tumor cells. They are involved in many physiological and pathological processes, such as inflammation and angiogenesis. In this context, it is paramount to explore the advancements made so far in elucidating the roles that MCs have in skin cancer because they might provide valuable therapeutic targets in the future. Controversial and conflicting results were obtained across the studies examined.
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Affiliation(s)
- Silvia Alda
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center Timişoara, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Raluca Amalia Ceausu
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center Timişoara, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania;
| | - Pusa Nela Gaje
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center Timişoara, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Marius Raica
- Department of Microscopic Morphology/Histology, Angiogenesis Research Center Timişoara, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
| | - Raluca Mioara Cosoroaba
- Department of Management, Legislation and Communication in Dental Medicine, First Department of Dentistry, Faculty of Dental Medicine, Victor Babeş University of Medicine and Pharmacy, Timişoara, Romania
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24
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Xie Z, Niu L, Zheng G, Du K, Dai S, Li R, Dan H, Duan L, Wu H, Ren G, Dou X, Feng F, Zhang J, Zheng J. Single-cell analysis unveils activation of mast cells in colorectal cancer microenvironment. Cell Biosci 2023; 13:217. [PMID: 38031173 PMCID: PMC10687892 DOI: 10.1186/s13578-023-01144-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 10/09/2023] [Indexed: 12/01/2023] Open
Abstract
The role of mast cells (MCs) in colorectal cancer (CRC) remains unclear, and a comprehensive single-cell study on CRC MCs has not been conducted. This study used a multi-omics approach, integrating single-cell sequencing, spatial transcriptomics, and bulk tissue sequencing data to investigate the heterogeneity and impact of MCs in CRC. Five MC signature genes (TPSAB1, TPSB2, CPA3, HPGDS, and MS4A2) were identified, and their average expression was used as a marker of MCs. The MC density was found to be lower in CRC compared to normal tissue, but MCs in CRC demonstrated distinct activation features. Activated MCs were defined by high expression of receptors and MC mediators, while resting MCs had low expression. Most genes, including the five MC signature genes, were expressed at higher levels in activated MCs. The MC signature was linked to a better prognosis in both CRC and pan-cancer patient cohorts. Elevated KITLG expression was observed in fibroblasts and endothelial cells in CRC samples compared to normal tissue, and co-localization of MCs with these cell types was revealed by spatial transcriptome analysis. In conclusion, this study finds decreased MC density in CRC compared to normal tissue, but highlights a shift in MC phenotype from CMA1high resting cells to activated TPSAB1high, CPA3high, and KIThigh cells. The elevated KITLG expression in the tumor microenvironment's fibroblasts and endothelial cells may activate MCs through the KITLG-KIT axis, potentially suppressing tumor progression.
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Affiliation(s)
- Zhenyu Xie
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China
| | - Liaoran Niu
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China
| | - Gaozan Zheng
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China
| | - Kunli Du
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China
| | - Songchen Dai
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, 110016, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, 110016, China
| | - Ruikai Li
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China
| | - Hanjun Dan
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China
| | - Lili Duan
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China
| | - Hongze Wu
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China
| | - Guangming Ren
- Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Xinyu Dou
- Xi'an Medical University, Xi'an, Shaanxi, 710021, China
| | - Fan Feng
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China.
| | - Jian Zhang
- The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China.
| | - Jianyong Zheng
- The State Key Laboratory of Cancer Biology, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 169 Changle Road, Xi'an, Shaanxi, 710032, China.
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25
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Wang J, Li J. Research progress in the pathogenesis of chronic urticaria. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2023; 48:1602-1610. [PMID: 38432889 PMCID: PMC10929888 DOI: 10.11817/j.issn.1672-7347.2023.230037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Indexed: 03/05/2024]
Abstract
Chronic urticaria is very common in clinic, but its pathogenesis is not fully elucidated. Most patients can't find the exact cause, resulting in misdiagnosis or delayed treatment. Previous studies have found that mast cell activation is the central link in the pathogenesis of chronic urticaria. Genetics, autoimmune, coagulation disorders, and infection may also be involved in the pathophysiological process of chronic urticaria. With the deepening of research, more immune and non-immune mechanisms have been gradually revealed in the pathogenesis of chronic urticaria, such as the interaction of immune cells in the microenvironment of urticaria, intestinal flora and metabolism, neuroimmunity, environmental factors and hormones. Clarifying the pathogenesis of chronic urticaria will help to find more treatment targets and provide more diversified ideas for clinical diagnosis and treatment.
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Affiliation(s)
- Jiayi Wang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Jie Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
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26
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Riihimäki M, Fegraeus K, Nordlund J, Waern I, Wernersson S, Akula S, Hellman L, Raine A. Single-cell transcriptomics delineates the immune cell landscape in equine lower airways and reveals upregulation of FKBP5 in horses with asthma. Sci Rep 2023; 13:16261. [PMID: 37758813 PMCID: PMC10533524 DOI: 10.1038/s41598-023-43368-4] [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: 04/02/2023] [Accepted: 09/22/2023] [Indexed: 09/29/2023] Open
Abstract
Equine asthma (EA) is a heterogenous, complex disease, with a significant negative impact on horse welfare and performance. EA and human asthma share fundamental similarities, making EA a useful model for studying the disease. One relevant sample type for investigating chronic lung inflammation is bronchoalveolar lavage fluid (BALF), which provides a snapshot of the immune cells present in the alveolar space. To investigate the immune cell landscape of the respiratory tract in horses with mild-to-moderate equine asthma (mEA) and healthy controls, single-cell RNA sequencing was conducted on equine BALF cells. We characterized the major immune cell populations present in equine BALF, as well as subtypes thereof. Interestingly, the most significantly upregulated gene discovered in cases of mEA was FKBP5, a chaperone protein involved in regulating the activity of the glucocorticoid receptor.
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Affiliation(s)
- Miia Riihimäki
- Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Kim Fegraeus
- Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Jessica Nordlund
- Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Ida Waern
- Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Sara Wernersson
- Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Srinivas Akula
- Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Lars Hellman
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Amanda Raine
- Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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27
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Dileepan KN, Raveendran VV, Sharma R, Abraham H, Barua R, Singh V, Sharma R, Sharma M. Mast cell-mediated immune regulation in health and disease. Front Med (Lausanne) 2023; 10:1213320. [PMID: 37663654 PMCID: PMC10470157 DOI: 10.3389/fmed.2023.1213320] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/17/2023] [Indexed: 09/05/2023] Open
Abstract
Mast cells are important components of the immune system, and they perform pro-inflammatory as well as anti-inflammatory roles in the complex process of immune regulation in health and disease. Because of their strategic perivascular localization, sensitivity and adaptability to the microenvironment, and ability to release a variety of preformed and newly synthesized effector molecules, mast cells perform unique functions in almost all organs. Additionally, Mast cells express a wide range of surface and cytoplasmic receptors which enable them to respond to a variety of cytokines, chemicals, and pathogens. The mast cell's role as a cellular interface between external and internal environments as well as between vasculature and tissues is critical for protection and repair. Mast cell interactions with different immune and nonimmune cells through secreted inflammatory mediators may also turn in favor of disease promoting agents. First and forefront, mast cells are well recognized for their multifaceted functions in allergic diseases. Reciprocal communication between mast cells and endothelial cells in the presence of bacterial toxins in chronic/sub-clinical infections induce persistent vascular inflammation. We have shown that mast cell proteases and histamine induce endothelial inflammatory responses that are synergistically amplified by bacterial toxins. Mast cells have been shown to exacerbate vascular changes in normal states as well as in chronic or subclinical infections, particularly among cigarette smokers. Furthermore, a potential role of mast cells in SARS-CoV-2-induced dysfunction of the capillary-alveolar interface adds to the growing understanding of mast cells in viral infections. The interaction between mast cells and microglial cells in the brain further highlights their significance in neuroinflammation. This review highlights the significant role of mast cells as the interface that acts as sensor and early responder through interactions with cells in systemic organs and the nervous system.
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Affiliation(s)
- Kottarappat N. Dileepan
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Vineesh V. Raveendran
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Rishi Sharma
- Department of Medicine, School of Medicine, University of Missouri, Kansas City, MO, United States
| | - Harita Abraham
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Rajat Barua
- Cardiology Section, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
| | - Vikas Singh
- Neurology Section, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
| | - Ram Sharma
- Research and Development Service, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
| | - Mukut Sharma
- Research and Development Service, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
- Midwest Veterans’ Biomedical Research Foundation (MVBRF), Kansas City VA Medical Center, Kansas, MO, United States
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28
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Bakhashab S, Banafea GH, Ahmed F, Alsehli H, AlShaibi HF, Bagatian N, Subhi O, Gauthaman K, Rasool M, Schulten HJ, Pushparaj PN. Characterization of human umbilical cord blood-derived mast cells using high-throughput expression profiling and next-generation knowledge discovery platforms. Exp Mol Pathol 2023; 132-133:104867. [PMID: 37634863 DOI: 10.1016/j.yexmp.2023.104867] [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: 07/10/2023] [Revised: 08/09/2023] [Accepted: 08/14/2023] [Indexed: 08/29/2023]
Abstract
Mast cells (MCs) are tissue-resident innate immune cells that express the high-affinity receptor for immunoglobulin E and are responsible for host defense and an array of diseases related to immune system. We aimed in this study to characterize the pathways and gene signatures of human cord blood-derived MCs (hCBMCs) in comparison to cells originating from CD34- progenitors using next-generation knowledge discovery methods. CD34+ cells were isolated from human umbilical cord blood using magnetic activated cell sorting and differentiated into MCs with rhIL-6 and rhSCF supplementation for 6-8 weeks. The purity of hCBMCs was analyzed by flow cytometry exhibiting the surface markers CD117+CD34-CD45-CD23-FcεR1αdim. Total RNA from hCBMCs and CD34- cells were isolated and hybridized using microarray. Differentially expressed genes were analyzed using iPathway Guide and Pre-Ranked Gene Set Enrichment Analysis. Next-generation knowledge discovery platforms revealed MC-specific gene signatures and molecular pathways enriched in hCBMCs and pertain the immunological response repertoire.
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Affiliation(s)
- Sherin Bakhashab
- Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
| | - Ghalya H Banafea
- Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Farid Ahmed
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Haneen Alsehli
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Centre for Stem Cells & Regenerative Medicine, King's College London, UK
| | - Huda F AlShaibi
- Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Nadia Bagatian
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ohoud Subhi
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Kalamegam Gauthaman
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Mahmood Rasool
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hans-Juergen Schulten
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Peter Natesan Pushparaj
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
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29
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Mihele DM, Nistor PA, Bruma G, Mitran CI, Mitran MI, Condrat CE, Tovaru M, Tampa M, Georgescu SR. Mast Cell Activation Syndrome Update-A Dermatological Perspective. J Pers Med 2023; 13:1116. [PMID: 37511729 PMCID: PMC10381535 DOI: 10.3390/jpm13071116] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/26/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Mast cells (MCs) are infamous for their role in potentially fatal anaphylaxis reactions. In the last two decades, a more complex picture has emerged, as it has become obvious that MCs are much more than just IgE effectors of anaphylaxis. MCs are defenders against a host of infectious and toxic aggressions (their interactions with other components of the immune system are not yet fully understood) and after the insult has ended, MCs continue to play a role in inflammation regulation and tissue repair. Unfortunately, MC involvement in pathology is also significant. Apart from their role in allergies, MCs can proliferate clonally to produce systemic mastocytosis. They have also been implicated in excessive fibrosis, keloid scaring, graft rejection and chronic inflammation, especially at the level of the skin and gut. In recent years, the term MC activation syndrome (MCAS) was proposed to account for symptoms caused by MC activation, and clear diagnostic criteria have been defined. However, not all authors agree with these criteria, as some find them too restrictive, potentially leaving much of the MC-related pathology unaccounted for. Here, we review the current knowledge on the physiological and pathological roles of MCs, with a dermatological emphasis, and discuss the MCAS classification.
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Affiliation(s)
- Dana Mihaela Mihele
- Dermatology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Paul Andrei Nistor
- Internal Medicine Department, Emergency University Hospital Bucharest, 169 Independence Blvd, 050098 Bucharest, Romania
| | - Gabriela Bruma
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Cristina Iulia Mitran
- Microbiology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Madalina Irina Mitran
- Microbiology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Carmen Elena Condrat
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania
- Department of Obstetrics and Gynecology, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
| | - Mihaela Tovaru
- Dermatology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Mircea Tampa
- Dermatology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
| | - Simona Roxana Georgescu
- Dermatology Department, Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, Romania
- Dermatology Department, Victor Babes Clinical Hospital of Infectious and Tropical Diseases, 030303 Bucharest, Romania
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30
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Ribatti D, d'Amati A. Hematopoiesis and Mast Cell Development. Int J Mol Sci 2023; 24:10679. [PMID: 37445862 DOI: 10.3390/ijms241310679] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 06/22/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Hematopoietic stem cells (HSCs) are defined based on their capacity to replenish themselves (self-renewal) and give rise to all mature hematopoietic cell types (multi-lineage differentiation) over their lifetime. HSCs are mainly distributed in the bone marrow during adult life, harboring HSC populations and a hierarchy of different kinds of cells contributing to the "niche" that supports HSC regulation, myelopoiesis, and lymphopoiesis. In addition, HSC-like progenitors, innate immune cell precursors such as macrophages, mast cells, natural killer cells, innate lymphoid cells, and megakaryocytes and erythrocyte progenitor cells are connected by a series of complex ontogenic relationships. The first source of mast cells is the extraembryonic yolk sac, on embryonic day 7. Mast cell progenitors circulate and enter peripheral tissues where they complete their differentiation. Embryonic mast cell populations are gradually replaced by definitive stem cell-derived progenitor cells. Thereafter, mast cells originate from the bone marrow, developing from the hematopoietic stem cells via multipotent progenitors, common myeloid progenitors, and granulocyte/monocyte progenitors. In this review article, we summarize the knowledge on mast cell sources, particularly focusing on the complex and multifaceted mechanisms intervening between the hematopoietic process and the development of mast cells.
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Affiliation(s)
- Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience, School of Medicine, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Antonio d'Amati
- Department of Translational Biomedicine and Neuroscience, School of Medicine, University of Bari "Aldo Moro", 70124 Bari, Italy
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31
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Raj S, Unsworth LD. Targeting active sites of inflammation using inherent properties of tissue-resident mast cells. Acta Biomater 2023; 159:21-37. [PMID: 36657696 DOI: 10.1016/j.actbio.2023.01.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 12/12/2022] [Accepted: 01/10/2023] [Indexed: 01/18/2023]
Abstract
Mast cells play a pivotal role in initiating and directing host's immune response. They reside in tissues that primarily interface with the external environment. Activated mast cells respond to environmental cues throughout acute and chronic inflammation through releasing immune mediators via rapid degranulation, or long-term de novo expression. Mast cell activation results in the rapid release of a variety of unique enzymes and reactive oxygen species. Furthermore, the increased density of mast cell unique receptors like mas related G protein-coupled receptor X2 also characterizes the inflamed tissues. The presence of these molecules (either released mediators or surface receptors) are particular to the sites of active inflammation, and are a result of mast cell activation. Herein, the molecular design principles for capitalizing on these novel mast cell properties is discussed with the goal of manipulating localized inflammation. STATEMENT OF SIGNIFICANCE: Mast cells are immune regulating cells that play a crucial role in both innate and adaptive immune responses. The activation of mast cells causes the release of multiple unique profiles of biomolecules, which are specific to both tissue and disease. These unique characteristics are tightly regulated and afford a localized stimulus for targeting inflammatory diseases. Herein, these important mast cell attributes are discussed in the frame of highlighting strategies for the design of bioresponsive functional materials to target regions of inflammations.
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Affiliation(s)
- Shammy Raj
- Department of Chemical and Materials Engineering, Donadeo Innovation Centre for Engineering, 9211-116 Street NW, University of Alberta, Edmonton, AB, T6G1H9, Canada
| | - Larry D Unsworth
- Department of Chemical and Materials Engineering, Donadeo Innovation Centre for Engineering, 9211-116 Street NW, University of Alberta, Edmonton, AB, T6G1H9, Canada.
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32
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Rische CH, Thames AN, Krier-Burris RA, O’Sullivan JA, Bochner BS, Scott EA. Drug delivery targets and strategies to address mast cell diseases. Expert Opin Drug Deliv 2023; 20:205-222. [PMID: 36629456 PMCID: PMC9928520 DOI: 10.1080/17425247.2023.2166926] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 11/10/2022] [Accepted: 01/06/2023] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Current and developing mast cell therapeutics are reliant on small molecule drugs and biologics, but few are truly selective for mast cells. Most have cellular and disease-specific limitations that require innovation to overcome longstanding challenges to selectively targeting and modulating mast cell behavior. This review is designed to serve as a frame of reference for new approaches that utilize nanotechnology or combine different drugs to increase mast cell selectivity and therapeutic efficacy. AREAS COVERED Mast cell diseases include allergy and related conditions as well as malignancies. Here, we discuss the targets of existing and developing therapies used to treat these disease pathologies, classifying them into cell surface, intracellular, and extracellular categories. For each target discussed, we discuss drugs that are either the current standard of care, under development, or have indications for potential use. Finally, we discuss how novel technologies and tools can be used to take existing therapeutics to a new level of selectivity and potency against mast cells. EXPERT OPINION There are many broadly and very few selectively targeted therapeutics for mast cells in allergy and malignant disease. Combining existing targeting strategies with technology like nanoparticles will provide novel platforms to treat mast cell disease more selectively.
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Affiliation(s)
- Clayton H. Rische
- Northwestern University McCormick School of Engineering, Department of Biomedical Engineering, Evanston, IL, USA
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
| | - Ariel N. Thames
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
- Northwestern University McCormick School of Engineering, Department of Chemical and Biological Engineering, Evanston, IL, USA
| | - Rebecca A. Krier-Burris
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
| | - Jeremy A. O’Sullivan
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
| | - Bruce S. Bochner
- Northwestern University Feinberg School of Medicine, Division of Allergy and Immunology, Chicago, IL, USA
| | - Evan A. Scott
- Northwestern University McCormick School of Engineering, Department of Biomedical Engineering, Evanston, IL, USA
- Northwestern University Feinberg School of Medicine, Department of Microbiolgy-Immunology, Chicago, IL, USA
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House Dust Mite and Cat Dander Extract Induce Asthma-Like Histopathology with an Increase of Mucosal Mast Cells in a Guinea Pig Model. J Immunol Res 2023; 2023:9393497. [PMID: 36761882 PMCID: PMC9904926 DOI: 10.1155/2023/9393497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 02/04/2023] Open
Abstract
Background Asthma is a chronic inflammatory disease with structural changes in the lungs defined as airway remodelling. Mast cell responses are important in asthma as they, upon activation, release mediators inducing bronchoconstriction, inflammatory cell recruitment, and often remodelling of the airways. As guinea pigs exhibit anatomical, physiological, and pharmacological features resembling human airways, including mast cell distribution and mediator release, we evaluated the effect of extracts from two common allergens, house dust mite (HDM) and cat dander (CDE), on histopathological changes and the composition of tryptase- and chymase-positive mast cells in the guinea pig lungs. Methods Guinea pigs were exposed intranasally to HDM or CDE for 4, 8, and 12 weeks, and airway histology was examined at each time point. Hematoxylin and eosin, Picro-Sirius Red, and Periodic Acid-Schiff staining were performed to evaluate airway inflammation, collagen deposition, and mucus-producing cells. In addition, Astra blue and immunostaining against tryptase and chymase were used to visualize mast cells. Results Repetitive administration of HDM or CDE led to the accumulation of inflammatory cells into the proximal and distal airways as well as increased airway smooth muscle mass. HDM exposure caused subepithelial collagen deposition and mucus cell hyperplasia at all three time points, whereas CDE exposure only caused these effects at 8 and 12 weeks. Both HDM and CDE induced a substantial increase in mast cells after 8 and 12 weeks of challenges. This increase was primarily due to mast cells expressing tryptase, but not chymase, thus indicating mucosal mast cells. Conclusions We here show that exposure to HDM and CDE elicits asthma-like histopathology in guinea pigs with infiltration of inflammatory cells, airway remodelling, and accumulation of primarily mucosal mast cells. The results together encourage the use of HDM and CDE allergens for the stimulation of a clinically relevant asthma model in guinea pigs.
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Woodrow JS, Hines M, Sommardahl C, Flatland B, Lo Y, Wang Z, Sheats MK, Lennon EM. Initial investigation of molecular phenotypes of airway mast cells and cytokine profiles in equine asthma. Front Vet Sci 2023; 9:997139. [PMID: 36713876 PMCID: PMC9875299 DOI: 10.3389/fvets.2022.997139] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 12/23/2022] [Indexed: 01/13/2023] Open
Abstract
Equine asthma is a naturally occurring lung disease characterized by chronic, partially reversible airway obstruction, pulmonary remodeling, and lower airway inflammation. Asthma is currently divided into two major groups, mild to moderate asthma (mEA) and severe asthma (sEA), but further subtyping by phenotype (i.e., clinical presentation) and/or endotype (i.e., cellular mechanisms) may be warranted. For this study, we were interested in further investigation of cellular and inflammatory characteristics of EA, including airway mast cells. The purpose of this study was to: (1) compare mast cell protease mRNA expression between healthy and asthmatic horses, (2) analyze the cytokine profile present in BALF of currently defined equine asthma groups, and (3) use these data to evaluate potential biomarkers of defined asthma groups. We hypothesized that there would be significant differences in the cellular mast cell phenotypes (i.e., mucosal vs. connective tissue) and cytokine profiles in the BALF of asthmatic vs. healthy horses and across asthma groups. We assert these characteristics may inform additional subtypes of equine asthma. Adult horses were recruited from the institution's teaching herd and clinical caseload. Mast cell protease gene expression of the BALF cellular component and multiplex bead immunoassay for cytokine concentrations in the BALF supernatant were investigated. Airway mast cells primarily expressed tryptase, with low levels of chymase. No significant changes in protease expression were detected across groups. Horses with severe asthma had increased TNF-α, CXCL-8, and IFN-γ concentrations in BALF supernatant. Multidimensional analysis demonstrated healthy and mEA horses have overlapping characteristics, with sEA separating from the other groups. This difference was primarily due to BALF neutrophil and lymphocyte concentrations. These study results further inform understanding of EA immunopathology, and future studies designed to investigate asthma phenotypes and endotypes. Ultimately, a better understanding of these groups could help identify novel therapeutic strategies.
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Affiliation(s)
- Jane S. Woodrow
- Department of Comparative and Experimental Medicine, College of Veterinary Medicine, University of Tennessee, Knoxville, Knoxville, TN, United States,Department of Clinical Sciences and Advanced Medicine, College of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Melissa Hines
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Carla Sommardahl
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Bente Flatland
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Yancy Lo
- Bioinformatics Core, Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, United States
| | - Zhiping Wang
- Bioinformatics Core, Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, United States
| | - Mary Katie Sheats
- Department of Clinical Sciences, Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Elizabeth M. Lennon
- Department of Clinical Sciences and Advanced Medicine, College of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States,*Correspondence: Elizabeth M. Lennon ✉
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van der Elst G, Varol H, Hermans M, Baan CC, Duong-van Huyen JP, Hesselink DA, Kramann R, Rabant M, Reinders MEJ, von der Thüsen JH, van den Bosch TPP, Clahsen-van Groningen MC. The mast cell: A Janus in kidney transplants. Front Immunol 2023; 14:1122409. [PMID: 36891297 PMCID: PMC9986315 DOI: 10.3389/fimmu.2023.1122409] [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: 12/12/2022] [Accepted: 01/30/2023] [Indexed: 02/22/2023] Open
Abstract
Mast cells (MCs) are innate immune cells with a versatile set of functionalities, enabling them to orchestrate immune responses in various ways. Aside from their known role in allergy, they also partake in both allograft tolerance and rejection through interaction with regulatory T cells, effector T cells, B cells and degranulation of cytokines and other mediators. MC mediators have both pro- and anti-inflammatory actions, but overall lean towards pro-fibrotic pathways. Paradoxically, they are also seen as having potential protective effects in tissue remodeling post-injury. This manuscript elaborates on current knowledge of the functional diversity of mast cells in kidney transplants, combining theory and practice into a MC model stipulating both protective and harmful capabilities in the kidney transplant setting.
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Affiliation(s)
- G van der Elst
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - H Varol
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - M Hermans
- Department of Internal Medicine, Division of Allergy and Clinical Immunology, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - C C Baan
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | | | - D A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - R Kramann
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.,Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - M Rabant
- Department of Pathology, Necker Hospital, APHP, Paris, France
| | - M E J Reinders
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - J H von der Thüsen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - T P P van den Bosch
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands
| | - M C Clahsen-van Groningen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, Netherlands.,Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
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Rönnberg E, Ravindran A, Mazzurana L, Gong Y, Säfholm J, Lorent J, Dethlefsen O, Orre AC, Al-Ameri M, Adner M, Dahlén SE, Dahlin JS, Mjösberg J, Nilsson G. Analysis of human lung mast cells by single cell RNA sequencing. Front Immunol 2023; 14:1151754. [PMID: 37063885 PMCID: PMC10100501 DOI: 10.3389/fimmu.2023.1151754] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/15/2023] [Indexed: 04/18/2023] Open
Abstract
Mast cells are tissue-resident cells playing major roles in homeostasis and disease conditions. Lung mast cells are particularly important in airway inflammatory diseases such as asthma. Human mast cells are classically divided into the subsets MCT and MCTC, where MCT express the mast cell protease tryptase and MCTC in addition express chymase, carboxypeptidase A3 (CPA3) and cathepsin G. Apart from the disctintion of the MCT and MCTC subsets, little is known about the heterogeniety of human lung mast cells and a deep analysis of their heterogeniety has previously not been performed. We therefore performed single cell RNA sequencing on sorted human lung mast cells using SmartSeq2. The mast cells showed high expression of classical mast cell markers. The expression of several individual genes varied considerably among the cells, however, no subpopulations were detected by unbiased clustering. Variable genes included the protease-encoding transcripts CMA1 (chymase) and CTSG (cathepsin G). Human lung mast cells are predominantly of the MCT subset and consistent with this, the expression of CMA1 was only detectable in a small proportion of the cells, and correlated moderately to CTSG. However, in contrast to established data for the protein, CPA3 mRNA was high in all cells and the correlation of CPA3 to CMA1 was weak.
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Affiliation(s)
- Elin Rönnberg
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
- *Correspondence: Elin Rönnberg, ; Gunnar Nilsson,
| | - Avinash Ravindran
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Luca Mazzurana
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Yitao Gong
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
| | - Jesper Säfholm
- Unit for Experimental Asthma and Allergy Research Centre for Allergy Research, The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Julie Lorent
- National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Stockholm University, Stockholm, Sweden
| | - Olga Dethlefsen
- National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Stockholm University, Stockholm, Sweden
| | - Ann-Charlotte Orre
- Thoracic Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Mamdoh Al-Ameri
- Thoracic Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Mikael Adner
- Unit for Experimental Asthma and Allergy Research Centre for Allergy Research, The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sven-Erik Dahlén
- Unit for Experimental Asthma and Allergy Research Centre for Allergy Research, The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Joakim S. Dahlin
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
| | - Jenny Mjösberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Gunnar Nilsson
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- *Correspondence: Elin Rönnberg, ; Gunnar Nilsson,
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37
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Mast cell chymase regulates extracellular matrix remodeling-related events in primary human small airway epithelial cells. J Allergy Clin Immunol 2022; 150:1534-1544. [PMID: 35779668 DOI: 10.1016/j.jaci.2022.05.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Mast cells are implicated in the pathogenesis of asthma, but the underlying mechanisms are not fully elucidated. Under asthmatic conditions, mast cells can relocalize to the epithelial layer and may thereby affect the functional properties of the airway epithelial cells. OBJECTIVES Activated mast cells release large quantities of proteases from their secretory granules, including chymase and tryptase. Here we investigated whether these proteases may affect airway epithelial cells. METHODS Primary small airway epithelial cells were treated with tryptase or chymase, and the effects on epithelial cell viability, proliferation, migration, cytokine output, and transcriptome were evaluated. RESULTS Airway epithelial cells were relatively refractory to tryptase. In contrast, chymase had extensive effects on multiple features of the epithelial cells, with a particular emphasis on processes related to extracellular matrix (ECM) remodeling. These included suppressed expression of ECM-related genes such as matrix metalloproteinases, which was confirmed at the protein level. Further, chymase suppressed the expression of the fibronectin gene and also caused degradation of fibronectin released by the epithelial cells. Chymase was also shown to suppress the migratory capacity of the airway epithelial cells and to degrade the cell-cell contact protein E-cadherin on the epithelial cell surface. CONCLUSION Our findings suggest that chymase may affect the regulation of ECM remodeling events mediated by airway epithelial cells, with implications for the impact of mast cells in inflammatory lung diseases such as asthma.
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38
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Akula S, Riihimäki M, Waern I, Åbrink M, Raine A, Hellman L, Wernersson S. Quantitative Transcriptome Analysis of Purified Equine Mast Cells Identifies a Dominant Mucosal Mast Cell Population with Possible Inflammatory Functions in Airways of Asthmatic Horses. Int J Mol Sci 2022; 23:ijms232213976. [PMID: 36430453 PMCID: PMC9692376 DOI: 10.3390/ijms232213976] [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: 10/14/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Asthma is a chronic inflammatory airway disease and a serious health problem in horses as well as in humans. In humans and mice, mast cells (MCs) are known to be directly involved in asthma pathology and subtypes of MCs accumulate in different lung and airway compartments. The role and phenotype of MCs in equine asthma has not been well documented, although an accumulation of MCs in bronchoalveolar lavage fluid (BALF) is frequently seen. To characterize the phenotype of airway MCs in equine asthma we here developed a protocol, based on MACS Tyto sorting, resulting in the isolation of 92.9% pure MCs from horse BALF. We then used quantitative transcriptome analyses to determine the gene expression profile of the purified MCs compared with total BALF cells. We found that the MCs exhibited a protease profile typical for the classical mucosal MC subtype, as demonstrated by the expression of tryptase (TPSB2) alone, with no expression of chymase (CMA1) or carboxypeptidase A3 (CPA3). Moreover, the expression of genes involved in antigen presentation and complement activation strongly implicates an inflammatory role for these MCs. This study provides a first insight into the phenotype of equine MCs in BALF and their potential role in the airways of asthmatic horses.
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Affiliation(s)
- Srinivas Akula
- Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, P.O. Box 7011, SE-750 07 Uppsala, Sweden
| | - Miia Riihimäki
- Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden
| | - Ida Waern
- Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, P.O. Box 7011, SE-750 07 Uppsala, Sweden
| | - Magnus Åbrink
- Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden
| | - Amanda Raine
- Science for Life Laboratory, Department of Medical Sciences, Uppsala University, SE-752 36 Uppsala, Sweden
| | - Lars Hellman
- Department of Cell and Molecular Biology, The Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden
| | - Sara Wernersson
- Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, P.O. Box 7011, SE-750 07 Uppsala, Sweden
- Correspondence: ; Tel.: +46-(0)1-8672-112
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39
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Abstract
PURPOSE OF REVIEW This review will present what is known from recent research on the involvement of mast cells in eosinophilic esophagitis and identify questions requiring further investigation. RECENT FINDINGS In the adults and children with eosinophilic esophagitis, there is increasing evidence that mastocytosis can persist, despite resolution of eosinophilia and is associated with persistent mucosal abnormalities and symptoms. Despite, treatment mast cells have an activated transcriptome. Mast cells likely contribute to epithelial barrier dysfunction, smooth muscle hypertrophy and contraction, and subepithelial fibrosis. It remains unclear whether targeting MCs alone has therapeutic efficacy to improve tissue damage. SUMMARY Mast cells appear to play a key role in eosinophilic esophagitis and serve as a biomarker of mucosal healing in conjunction with eosinophils. Excessive mast cell activation likely contributes to tissue damage in eosinophilic esophagitis and need to be considered as a target of therapy along with eosinophils.
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40
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Schoots MH, Bezemer RE, Dijkstra T, Timmer B, Scherjon SA, Erwich JJHM, Hillebrands JL, Gordijn SJ, van Goor H, Prins JR. Distribution of decidual mast cells in fetal growth restriction and stillbirth at (near) term. Placenta 2022; 129:104-110. [PMID: 36283342 DOI: 10.1016/j.placenta.2022.10.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 10/08/2022] [Accepted: 10/11/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Placental pathology and pregnancy complications are associated with unfavorable regulation of the maternal immune system. Although much research has been performed towards the role of immune cells like macrophages and T cells in this context, little is known about the presence and function of mast cells (MC). MC can be sub classified in tryptase-positive (MCT) and tryptase- and chymase-positive (MCTC). This study investigates the presence of MC in the decidua of pregnancies complicated by fetal growth restriction (FGR) and stillbirth (SB). METHODS Placental tissue from FGR (n = 250), SB (n = 64) and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to the Amsterdam Placental Workshop Group criteria. Tissue sections were stained for tryptase and chymase. Decidual MC were counted manually, and the results were expressed as number of cells/mm2 decidual tissue. RESULTS A significant lower median number of MCTC was found in the decidua of FGR (0.40 per mm2; p < 0.001) and SB (0.51 per mm2; p < 0.05) compared to healthy controls (1.04 per mm2). No difference in MCT number (1.19 per mm2, 1.88 per mm2 and 1.37 per mm2 respectively) was seen between the groups. There was no difference in number of MCT and MCTC between placental pathological lesions. DISCUSSION Our findings suggest a shift in decidual MC balance towards MCT in pregnancy complications. No difference in numbers of MC subtypes was found to be related to histopathologic lesions.
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Affiliation(s)
- Mirthe H Schoots
- Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands.
| | - Romy E Bezemer
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - Tetske Dijkstra
- Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - Bert Timmer
- Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - Sicco A Scherjon
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - Jan Jaap H M Erwich
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - Jan-Luuk Hillebrands
- Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - Sanne J Gordijn
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - Harry van Goor
- Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
| | - Jelmer R Prins
- Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands
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Derakhshan T, Boyce JA, Dwyer DF. Defining mast cell differentiation and heterogeneity through single-cell transcriptomics analysis. J Allergy Clin Immunol 2022; 150:739-747. [PMID: 36205448 PMCID: PMC9547083 DOI: 10.1016/j.jaci.2022.08.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 11/23/2022]
Abstract
Mast cells (MCs) are widely recognized as central effector cells during type 2 inflammatory reactions and thought to also play a role in innate immune responses, wound healing, and potentially cancer. Circulating progenitor cells mature to MCs in peripheral tissues, where they exhibit phenotypic and functional heterogeneity. This diversity likely originates from differences in MC development imprinted by microenvironmental signals. The advent of single-cell transcriptomics reveals MC diversity beyond differences in proteases that were classically used to identify MC phenotypes. Here, we provide an overview of the current knowledge on MC progenitor differentiation and characteristics, and MC heterogeneity seen in health versus disease, that are drastically advanced through single-cell profiling technologies. This powerful approach can provide detailed cellular maps of tissues to decipher the complex cellular functions and interactions that may lead to identifying candidate factors to target in therapies.
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Affiliation(s)
- Tahereh Derakhshan
- Jeff and Penny Vinik Center for Allergic Disease Research, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Harvard Medical School, Boston, Mass
| | - Joshua A Boyce
- Jeff and Penny Vinik Center for Allergic Disease Research, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Harvard Medical School, Boston, Mass
| | - Daniel F Dwyer
- Jeff and Penny Vinik Center for Allergic Disease Research, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Harvard Medical School, Boston, Mass.
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42
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Zhang Z, Ernst PB, Kiyono H, Kurashima Y. Utilizing mast cells in a positive manner to overcome inflammatory and allergic diseases. Front Immunol 2022; 13:937120. [PMID: 36189267 PMCID: PMC9518231 DOI: 10.3389/fimmu.2022.937120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 07/26/2022] [Indexed: 01/10/2023] Open
Abstract
Mast cells (MCs) are immune cells widely distributed in the body, accompanied by diverse phenotypes and functions. Committed mast cell precursors (MCPs) leave the bone marrow and enter the blood circulation, homing to peripheral sites under the control of various molecules from different microenvironments, where they eventually differentiate and mature. Partly attributable to the unique maturation mechanism, MCs display high functional heterogeneity and potentially plastic phenotypes. High plasticity also means that MCs can exhibit different subtypes to cope with different microenvironments, which we call “the peripheral immune education system”. Under the peripheral immune education system, MCs showed a new character from previous cognition in some cases, namely regulation of allergy and inflammation. In this review, we focus on the mucosal tissues, such as the gastrointestinal tract, to gain insights into the mechanism underlying the migration of MCs to the gut or other organs and their heterogeneity, which is driven by different microenvironments. In particular, the immunosuppressive properties of MCs let us consider that positively utilizing MCs may be a new way to overcome inflammatory and allergic disorders.
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Affiliation(s)
- Zhongwei Zhang
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Peter B Ernst
- Division of Comparative Pathology and Medicine, Department of Pathology, University of California, San Diego, San Diego, CA, United States
- Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, San Diego, CA, United States
- Department of Medicine, School of Medicine and Chiba University-University of California San Diego Center for Mucosal Immunology, Allergy and Vaccine (CU-UCSD), University of California, San Diego, San Diego, CA, United States
| | - Hiroshi Kiyono
- Department of Medicine, School of Medicine and Chiba University-University of California San Diego Center for Mucosal Immunology, Allergy and Vaccine (CU-UCSD), University of California, San Diego, San Diego, CA, United States
- Future Medicine Education and Research Organization, Chiba University, Chiba, Japan
- Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Human Mucosal Vaccinology, Chiba University Hospital, Chiba, Japan
- HanaVax Inc., Tokyo, Japan
- Mucosal Immunology and Allergy Therapeutics, Institute for Global Prominent Research, Chiba University, Chiba, Japan
- Research Institute of Disaster Medicine, Chiba University, Chiba, Japan
| | - Yosuke Kurashima
- Department of Innovative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
- Division of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Mucosal Immunology and Allergy Therapeutics, Institute for Global Prominent Research, Chiba University, Chiba, Japan
- Research Institute of Disaster Medicine, Chiba University, Chiba, Japan
- Institute for Advanced Academic Research, Chiba University, Chiba, Japan
- Empowering Next Generation Allergist/immunologist toward Global Excellence Task Force toward 2030 (ENGAGE)-Task Force, Tokyo, Japan
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Pongdee T, Castells M. Elevated Tryptase: Conditions and Pitfalls. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2022; 10:2436-2437. [PMID: 36087946 DOI: 10.1016/j.jaip.2022.06.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/27/2022] [Accepted: 06/27/2022] [Indexed: 06/15/2023]
Affiliation(s)
- Thanai Pongdee
- Division of Allergic Diseases, Mayo Clinic, Rochester, Minn
| | - Mariana Castells
- Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass.
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Elvevi A, Elli EM, Lucà M, Scaravaglio M, Pagni F, Ceola S, Ratti L, Invernizzi P, Massironi S. Clinical challenge for gastroenterologists-Gastrointestinal manifestations of systemic mastocytosis: A comprehensive review. World J Gastroenterol 2022; 28:3767-3779. [PMID: 36157547 PMCID: PMC9367223 DOI: 10.3748/wjg.v28.i29.3767] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 06/06/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Mastocytosis is a rare and heterogeneous disease characterized by various clinical and biological features that affect different prognoses and treatments. The disease is usually divided into 2 principal categories: cutaneous and systemic disease (SM). Clinical features can be related to mast cell (MC) mediator release or pathological MC infiltration. SM is a disease often hard to identify, and the diagnosis is based on clinical, biological, histological, and molecular criteria with different specialists involved in the patient's clinical work-up. Among all manifestations of the disease, gastrointestinal (GI) symptoms are common, being present in 14%-85% of patients, and can significantly impair the quality of life. Here we review the data regarding GI involvement in SM, in terms of clinical presentations, histological and endoscopic features, the pathogenesis of GI symptoms, and their treatment.
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Affiliation(s)
- Alessandra Elvevi
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Elena Maria Elli
- Hematology Division and Bone Marrow Transplant Unit, San Gerardo Hospital, Monza 20900, Italy
| | - Martina Lucà
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Miki Scaravaglio
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Fabio Pagni
- Department of Medicine and Surgery, Section of Pathology, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Stefano Ceola
- Department of Medicine and Surgery, Section of Pathology, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Laura Ratti
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Pietro Invernizzi
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
| | - Sara Massironi
- Gastroenterology Division, San Gerardo Hospital, University of Milano – Bicocca School of Medicine, Monza 20900, Italy
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Numata T, Harada K, Nakae S. Roles of Mast Cells in Cutaneous Diseases. Front Immunol 2022; 13:923495. [PMID: 35874756 PMCID: PMC9298983 DOI: 10.3389/fimmu.2022.923495] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/16/2022] [Indexed: 01/05/2023] Open
Abstract
Mast cells are present in all vascularized tissues of the body. They are especially abundant in tissues that are in frequent contact with the surrounding environment and act as potential sources of inflammatory and/or regulatory mediators during development of various infections and diseases. Mature mast cells’ cytoplasm contains numerous granules that store a variety of chemical mediators, cytokines, proteoglycans, and proteases. Mast cells are activated via various cell surface receptors, including FcϵRI, toll-like receptors (TLR), Mas-related G-protein-coupled receptor X2 (MRGPRX2), and cytokine receptors. IgE-mediated mast cell activation results in release of histamine and other contents of their granules into the extracellular environment, contributing to host defense against pathogens. TLRs, play a crucial role in host defense against various types of pathogens by recognizing pathogen-associated molecular patterns. On the other hand, excessive/inappropriate mast cell activation can cause various disorders. Here, we review the published literature regarding the known and potential inflammatory and regulatory roles of mast cells in cutaneous inflammation, including atopic dermatitis, psoriasis, and contact dermatitis GVHD, as well as in host defense against pathogens.
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Affiliation(s)
- Takafumi Numata
- Department of Dermatology, Tokyo Medical University, Tokyo, Japan
| | - Kazutoshi Harada
- Department of Dermatology, Tokyo Medical University, Tokyo, Japan
| | - Susumu Nakae
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan.,Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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46
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Hellman L, Akula S, Fu Z, Wernersson S. Mast Cell and Basophil Granule Proteases - In Vivo Targets and Function. Front Immunol 2022; 13:918305. [PMID: 35865537 PMCID: PMC9294451 DOI: 10.3389/fimmu.2022.918305] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/08/2022] [Indexed: 11/13/2022] Open
Abstract
Proteases are stored in very large amounts within abundant cytoplasmic granules of mast cells (MCs), and in lower amounts in basophils. These proteases are stored in their active form in complex with negatively charged proteoglycans, such as heparin and chondroitin sulfate, ready for rapid release upon MC and basophil activation. The absolute majority of these proteases belong to the large family of chymotrypsin related serine proteases. Three such enzymes are found in human MCs, a chymotryptic enzyme, the chymase, a tryptic enzyme, the tryptase and cathepsin G. Cathepsin G has in primates both chymase and tryptase activity. MCs also express a MC specific exopeptidase, carboxypeptidase A3 (CPA3). The targets and thereby the functions of these enzymes have for many years been the major question of the field. However, the fact that some of these enzymes have a relatively broad specificity has made it difficult to obtain reliable information about the biologically most important targets for these enzymes. Under optimal conditions they may cleave a relatively large number of potential targets. Three of these enzymes, the chymase, the tryptase and CPA3, have been shown to inactivate several venoms from snakes, scorpions, bees and Gila monster. The chymase has also been shown to cleave several connective tissue components and thereby to be an important player in connective tissue homeostasis. This enzyme can also generate angiotensin II (Ang II) by cleavage of Ang I and have thereby a role in blood pressure regulation. It also display anticoagulant activity by cleaving fibrinogen and thrombin. A regulatory function on excessive TH2 immunity has also been observed for both the chymase and the tryptase by cleavage of a highly selective set of cytokines and chemokines. The chymase also appear to have a protective role against ectoparasites such as ticks, mosquitos and leeches by the cleavage of their anticoagulant proteins. We here review the data that has accumulated concerning the potential in vivo functions of these enzymes and we discuss how this information sheds new light on the role of MCs and basophils in health and disease.
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Affiliation(s)
- Lars Hellman
- Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, Uppsala, Sweden
- *Correspondence: Lars Hellman,
| | - Srinivas Akula
- Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Zhirong Fu
- Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, Uppsala, Sweden
| | - Sara Wernersson
- Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden
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47
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Hasler WL, Grabauskas G, Singh P, Owyang C. Mast cell mediation of visceral sensation and permeability in irritable bowel syndrome. Neurogastroenterol Motil 2022; 34:e14339. [PMID: 35315179 PMCID: PMC9286860 DOI: 10.1111/nmo.14339] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/09/2021] [Accepted: 12/03/2021] [Indexed: 12/13/2022]
Abstract
Abnormalities of mast cell structure or function may play prominent roles in irritable bowel syndrome (IBS) symptom genesis. Mast cells show close apposition to sensory nerves and release bioactive substances in response to varied stimuli including infection, stress, and other neuroendocrine factors. Most studies focus on patients who develop IBS after enteric infection or who report diarrhea-predominant symptoms. Three topics underlying IBS pathogenesis have been emphasized in recent investigations. Visceral hypersensitivity to luminal stimulation is found in most IBS patients and may contribute to abdominal pain. Mast cell dysfunction also may disrupt epithelial barrier function which alters mucosal permeability potentially leading to altered bowel function and pain. Mast cell products including histamine, proteases, prostaglandins, and cytokines may participate in hypersensitivity and permeability defects, especially with diarrhea-predominant IBS. Recent experimental evidence indicates that the pronociceptive effects of histamine and proteases are mediated by the generation of prostaglandins in the mast cell. Enteric microbiome interactions including increased mucosal bacterial translocation may activate mast cells to elicit inflammatory responses underlying some of these pathogenic effects. Therapies to alter mast cell activity (mast cell stabilizers) or function (histamine antagonists) have shown modest benefits in IBS. Future investigations will seek to define patient subsets with greater potential to respond to therapies that address visceral hypersensitivity, epithelial permeability defects, and microbiome alterations secondary to mast cell dysfunction in IBS.
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Affiliation(s)
- William L. Hasler
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Gintautas Grabauskas
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Prashant Singh
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Chung Owyang
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
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Deodato D, Asad N, Dore TM. Discovery of 2-Thiobenzimidazoles as Noncovalent Inhibitors of SARS-CoV-2 Main Protease. Bioorg Med Chem Lett 2022; 72:128867. [PMID: 35760254 PMCID: PMC9225965 DOI: 10.1016/j.bmcl.2022.128867] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/03/2022] [Accepted: 06/21/2022] [Indexed: 11/18/2022]
Abstract
The discovery of antiviral agents against SARS-CoV-2 is an important step toward ending the COVID-19 pandemic and to tackle future outbreaks. In this context, the main protease (Mpro) represents an ideal target for developing coronavirus antivirals, being conserved among different strains and essential for survival. In this work, using in silico tools, we created and validated a docking protocol able to predict binders to the catalytic site of Mpro. The following structure-based virtual screening of a subset of the ZINC library (over 4.3 million unique structures), led to the identification of a hit compound having a 2-thiobenzimidazole scaffold. The inhibitory activity was confirmed using a FRET-based proteolytic assay against recombinant Mpro. Structure-activity relationships were obtained with the synthesis of a small library of analogs, guided by the analysis of the docking pose. Our efforts led to the identification of a micromolar Mpro inhibitor (IC50 = 14.9 µM) with an original scaffold possessing ideal drug-like properties (predicted using the QikProp function) and representing a promising lead for the development of a novel class of coronavirus antivirals.
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Affiliation(s)
- Davide Deodato
- New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Nadeem Asad
- New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates
| | - Timothy M Dore
- New York University Abu Dhabi, PO Box 129188, Abu Dhabi, United Arab Emirates; Department of Chemistry, University of Georgia, Athens, GA 30602, USA
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49
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Bahri R, Kiss O, Prise I, Garcia-Rodriguez KM, Atmoko H, Martínez-Gómez JM, Levesque MP, Dummer R, Smith MP, Wellbrock C, Bulfone-Paus S. Human Melanoma-Associated Mast Cells Display a Distinct Transcriptional Signature Characterized by an Upregulation of the Complement Component 3 That Correlates With Poor Prognosis. Front Immunol 2022; 13:861545. [PMID: 35669782 PMCID: PMC9163391 DOI: 10.3389/fimmu.2022.861545] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/23/2022] [Indexed: 11/13/2022] Open
Abstract
Cutaneous melanoma is one of the most aggressive human malignancies and shows increasing incidence. Mast cells (MCs), long-lived tissue-resident cells that are particularly abundant in human skin where they regulate both innate and adaptive immunity, are associated with melanoma stroma (MAMCs). Thus, MAMCs could impact melanoma development, progression, and metastasis by secreting proteases, pro-angiogenic factors, and both pro-inflammatory and immuno-inhibitory mediators. To interrogate the as-yet poorly characterized role of human MAMCs, we have purified MCs from melanoma skin biopsies and performed RNA-seq analysis. Here, we demonstrate that MAMCs display a unique transcriptome signature defined by the downregulation of the FcεRI signaling pathway, a distinct expression pattern of proteases and pro-angiogenic factors, and a profound upregulation of complement component C3. Furthermore, in melanoma tissue, we observe a significantly increased number of C3+ MCs in stage IV melanoma. Moreover, in patients, C3 expression significantly correlates with the MC-specific marker TPSAB1, and the high expression of both markers is linked with poorer melanoma survival. In vitro, we show that melanoma cell supernatants and tumor microenvironment (TME) mediators such as TGF-β, IL-33, and IL-1β induce some of the changes found in MAMCs and significantly modulate C3 expression and activity in MCs. Taken together, these data suggest that melanoma-secreted cytokines such as TGF-β and IL-1β contribute to the melanoma microenvironment by upregulating C3 expression in MAMCs, thus inducing an MC phenotype switch that negatively impacts melanoma prognosis.
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Affiliation(s)
- Rajia Bahri
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Division of Musculoskeletal & Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Orsolya Kiss
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Division of Musculoskeletal & Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Ian Prise
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Karen M. Garcia-Rodriguez
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Haris Atmoko
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Division of Musculoskeletal & Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Julia M. Martínez-Gómez
- Department of Dermatology, Skin Cancer Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Mitchell P. Levesque
- Department of Dermatology, Skin Cancer Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Reinhard Dummer
- Department of Dermatology, Skin Cancer Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael P. Smith
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Claudia Wellbrock
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Silvia Bulfone-Paus
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Division of Musculoskeletal & Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
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50
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Flow-based allergen testing: can mast cells beat basophils? Clin Chim Acta 2022; 532:64-71. [DOI: 10.1016/j.cca.2022.05.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/17/2022] [Accepted: 05/18/2022] [Indexed: 12/15/2022]
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