|
1
|
Hebda-Bauer EK, Hagenauer MH, Munro DB, Blandino P, Meng F, Arakawa K, Stead JDH, Chitre AS, Ozel AB, Mohammadi P, Watson SJ, Flagel SB, Li J, Palmer AA, Akil H. Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament. Front Mol Neurosci 2025; 18:1469467. [PMID: 40103584 PMCID: PMC11913853 DOI: 10.3389/fnmol.2025.1469467] [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: 07/23/2024] [Accepted: 02/05/2025] [Indexed: 03/20/2025] Open
Abstract
Externalizing and internalizing behavioral tendencies underlie many psychiatric and substance use disorders. These tendencies are associated with differences in temperament that emerge early in development via the interplay of genetic and environmental factors. To better understand the neurobiology of temperament, we have selectively bred rats for generations to produce two lines with highly divergent behavior: bred Low Responders (bLRs) are highly inhibited and anxious in novel environments, whereas bred High Responders (bHRs) are highly exploratory, sensation-seeking, and prone to drug-seeking behavior. Recently, we delineated these heritable differences by intercrossing bHRs and bLRs (F0-F1-F2) to produce a heterogeneous F2 sample with well-characterized lineage and behavior (exploratory locomotion, anxiety-like behavior, Pavlovian conditioning). The identified genetic loci encompassed variants that could influence behavior via many mechanisms, including proximal effects on gene expression. Here we measured gene expression in male and female F0s (n = 12 bHRs, 12 bLRs) and in a large sample of heterogeneous F2s (n = 250) using hippocampal RNA-Seq. This enabled triangulation of behavior with both genetic and functional genomic data to implicate specific genes and biological pathways. Our results show that bHR/bLR differential gene expression is robust, surpassing sex differences in expression, and predicts expression associated with F2 behavior. In F0 and F2 samples, gene sets related to growth/proliferation are upregulated with bHR-like behavior, whereas gene sets related to mitochondrial function, oxidative stress, and microglial activation are upregulated with bLR-like behavior. Integrating our F2 RNA-Seq data with previously-collected whole genome sequencing data identified genes with hippocampal expression correlated with proximal genetic variation (cis-expression quantitative trait loci or cis-eQTLs). These cis-eQTLs successfully predict bHR/bLR differential gene expression based on F0 genotype. Sixteen of these genes are associated with cis-eQTLs colocalized within loci we previously linked to behavior and are strong candidates for mediating the influence of genetic variation on behavioral temperament. Eight of these genes are related to bioenergetics. Convergence between our study and others targeting similar behavioral traits revealed five more genes consistently related to temperament. Overall, our results implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, thereby modulating vulnerability to psychiatric and addictive disorders.
Collapse
Affiliation(s)
- Elaine K Hebda-Bauer
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| | - Megan H Hagenauer
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| | - Daniel B Munro
- Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
- Seattle Children's Research Institute, University of Washington, Seattle, WA, United States
| | - Peter Blandino
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| | - Fan Meng
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| | - Keiko Arakawa
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| | - John D H Stead
- Department of Neuroscience, Carleton University, Ottawa, ON, Canada
| | - Apurva S Chitre
- Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
| | - A Bilge Ozel
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States
| | - Pejman Mohammadi
- Seattle Children's Research Institute, University of Washington, Seattle, WA, United States
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
| | - Stanley J Watson
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| | - Shelly B Flagel
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| | - Jun Li
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States
| | - Abraham A Palmer
- Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
- Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, United States
| | - Huda Akil
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States
| |
Collapse
|
|
2
|
Song M, Bai Y, Song F. High-fat diet and neuroinflammation: The role of mitochondria. Pharmacol Res 2025; 212:107615. [PMID: 39842474 DOI: 10.1016/j.phrs.2025.107615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/28/2024] [Accepted: 01/17/2025] [Indexed: 01/24/2025]
Abstract
In recent years, increasing evidence has supported that high-fat diet (HFD) can induce the chronic, low-grade neuroinflammation in the brain, which is closely associated with the impairment of cognitive function. As the key organelles responsible for energy metabolism in the cell, mitochondria are believed to involved in the pathogenesis of a variety of neurological disorders. This review summarizes the current progress in the field of the relationship between HFD exposure and neurodegenerative diseases, and outline the major routines of HFD induced neuroinflammation and its pathological significance in the pathogenesis of neurodegenerative diseases. Furthermore, the article highlights the pivotal role of mitochondrial dysfunction in driving the neuroinflammation in the setting of HFD. Danger-associated molecular patterns (DAMPs) from damaged mitochondria can activate innate immune signaling pathways, while mitochondrial dysfunction itself can lead to metabolic remodeling of inflammatory cells, thus inducing neuroinflammation. More importantly, mitochondrial damage, neuroinflammation, and insulin resistance caused by HFD form a mutually reinforcing vicious cycle, ultimately leading to the death of neurons and promoting the progression of neurodegenerative diseases. Thus, in-depth elucidation of the role and underlying mechanisms of mitochondrial dysfunction in HFD-induced metabolic disorders may not only expand our understanding of the mechanistic linkages between HFD and etiology of neurodegenerative diseases, but also help develop the specific strategies for the prevention and treatment of neurodegenerative diseases.
Collapse
Affiliation(s)
- Mingxue Song
- Department of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, China.
| | - Yao Bai
- NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing 100021, China.
| | - Fuyong Song
- Department of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, Shandong 250012, China.
| |
Collapse
|
|
3
|
Milosevic K, Milosevic A, Stevanovic I, Zivkovic A, Laketa D, Janjic MM, Bjelobaba I, Lavrnja I, Savic D. Agmatine suppresses glycolysis via the PI3K/Akt/mTOR/HIF-1α signaling pathway and improves mitochondrial function in microglia exposed to lipopolysaccharide. Biofactors 2025; 51:e2149. [PMID: 39888089 PMCID: PMC11780571 DOI: 10.1002/biof.2149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 11/22/2024] [Indexed: 02/01/2025]
Abstract
Modulating metabolic pathways in activated microglia can alter their phenotype, which is relevant in uncontrolled neuroinflammation as a component of various neurodegenerative diseases. Here, we investigated how pretreatment with agmatine, an endogenous polyamine, affects metabolic changes in an in vitro model of neuroinflammation, a murine microglial BV-2 cell line exposed to lipopolysaccharide (LPS). Hence, we analyzed gene expression using qPCR and protein levels using Western blot and ELISA. Microglial metabolic status was assessed by measuring lactate release and cellular ATP by enzymatic and luminescence spectrophotometry. Mitochondrial functionality was analyzed by fluorescent probes detecting mitochondrial membrane potential (mtMP) and superoxide production. Our findings suggest that kinase pathways associated with hypoxia-inducible factor-1α (HIF-1α) regulate energy metabolism in pro-inflammatory activated microglia. We have shown that LPS induces HIF-1α and genes for glucose transporter and glycolytic rate, increases lactate production and causes mitochondrial dysfunction, suggesting a metabolic shift towards glycolysis. Agmatine inhibits the PI3K/Akt pathway and negatively regulates mammalian target of rapamycin (mTOR) phosphorylation and HIF-1α levels, reducing lactate and tumor necrosis factor (TNF) production, which is supported by pharmacological blockade of PI3K. Pretreatment with agmatine also rescues mitochondrial function by counteracting the LPS-induced decline in mtMP and increase in mitochondrial superoxide, resulting in an anti-apoptotic effect. Agmatine alone increases intracellular ATP levels and maintains this effect even under pro-inflammatory conditions. Our study emphasizes the ability of agmatine to engage in metabolic reprogramming of pro-inflammatory microglia through increased ATP production and modulation of signaling pathway involved in promoting glycolysis and cytokine release.
Collapse
Affiliation(s)
- Katarina Milosevic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Ana Milosevic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Ivana Stevanovic
- Medical Faculty of the Military Medical AcademyUniversity of Defense in BelgradeBelgradeSerbia
| | - Anica Zivkovic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Danijela Laketa
- Department for General Physiology and BiophysicsFaculty of Biology, University of BelgradeBelgradeSerbia
| | - Marija M. Janjic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Ivana Bjelobaba
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Irena Lavrnja
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| | - Danijela Savic
- Department of NeurobiologyInstitute for Biological Research “Sinisa Stankovic”—National Institute of Republic of Serbia, University of BelgradeBelgradeSerbia
| |
Collapse
|
|
4
|
Kuang W, Huang J, Yang Y, Liao Y, Zhou Z, Liu Q, Wu H. Identification of markers correlating with mitochondrial function in myocardial infarction by bioinformatics. PLoS One 2024; 19:e0316463. [PMID: 39775580 PMCID: PMC11684664 DOI: 10.1371/journal.pone.0316463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Myocardial infarction (MI), one of the most serious cardiovascular diseases, is also affected by altered mitochondrial metabolism and immune status, but their crosstalk is poorly understood. In this paper, we use bioinformatics to explore key targets associated with mitochondrial metabolic function in MI. METHODS The datasets (GSE775, GSE183272 and GSE236374) were from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) in conjunction with mitochondrial gene data that were downloaded from the MitoCarta 3.0 database. Differentially expressed genes (DEGs) in the dataset were screened by ClusterGVis, Weighted Gene Co-Expression Network Analysis (WGCNA) and GEO2R, and functional enrichment was performed by Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genomes (KEGG). Then mitochondria-associated DEGs (MitoDEGs) were obtained. Protein-protein interaction (PPI) networks were constructed to identify central MitoDEGs that are strongly associated with MI. The Cytoscape and miRWalk databases were then used to predict the transcription factors and target miRNAs of the central MitoDEG, respectively. Finally, the mouse model has been established to demonstrate the expression of MitoDEGs and their association with cardiac function. RESULTS MitoDEGs in MI were mainly involved in mitochondrial function and adenosine triphosphate (ATP) synthesis pathways. The 10 MI-related hub MitoDEGs were then obtained by eight different algorithms. Immunoassays showed a significant increase in monocyte macrophage and T cell infiltration. According to animal experiments, the expression trends of the four hub MitoDEGs (Aco2, Atp5a1, Ndufs3, and Ndufv1) were verified to be consistent with the bioinformatics results. CONCLUSION Our study identified key genes (Aco2, Atp5a1, Ndufs3, and Ndufv1) associated with mitochondrial function in myocardial infarction.
Collapse
Affiliation(s)
- Wenlong Kuang
- Department of Cardiology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Cardiology, Wuhan No.1 Hospital, Wuhan, Hubei, China
| | - Jianwu Huang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yulu Yang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhua Liao
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zihua Zhou
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Liu
- Center for Reproductive Medicine, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hailang Wu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Engineering Research Center of Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
5
|
Ge Z, Chen Y, Ma L, Hu F, Xie L. Macrophage polarization and its impact on idiopathic pulmonary fibrosis. Front Immunol 2024; 15:1444964. [PMID: 39131154 PMCID: PMC11310026 DOI: 10.3389/fimmu.2024.1444964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 07/12/2024] [Indexed: 08/13/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lung disease that worsens over time, causing fibrosis in the lungs and ultimately resulting in respiratory failure and a high risk of death. Macrophages play a crucial role in the immune system, showing flexibility by transforming into either pro-inflammatory (M1) or anti-inflammatory (M2) macrophages when exposed to different stimuli, ultimately impacting the development of IPF. Recent research has indicated that the polarization of macrophages is crucial in the onset and progression of IPF. M1 macrophages secrete inflammatory cytokines and agents causing early lung damage and fibrosis, while M2 macrophages support tissue healing and fibrosis by releasing anti-inflammatory cytokines. Developing novel treatments for IPF relies on a thorough comprehension of the processes involved in macrophage polarization in IPF. The review outlines the regulation of macrophage polarization and its impact on the development of IPF, with the goal of investigating the possible therapeutic benefits of macrophage polarization in the advancement of IPF.
Collapse
Affiliation(s)
- Zhouling Ge
- Department of Respiratory Medicine, The Third Affiliated Hospital of Shanghai University (Wenzhou People’s Hospital), Wenzhou, China
| | - Yong Chen
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Leikai Ma
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fangjun Hu
- Department of Respiratory Medicine, The Third Affiliated Hospital of Shanghai University (Wenzhou People’s Hospital), Wenzhou, China
| | - Lubin Xie
- Department of Respiratory Medicine, The Third Affiliated Hospital of Shanghai University (Wenzhou People’s Hospital), Wenzhou, China
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
6
|
Yao Z, Zhu Z, Chen X, Li X. Ameliorative Effect of Raspberry Ketone on Hypothalamic Inflammation in High Fat Diet-Induced Obese Mice. J Nutr Sci Vitaminol (Tokyo) 2024; 70:496-502. [PMID: 39756970 DOI: 10.3177/jnsv.70.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
Abstract
This study aimed to investigate the regulatory effects of raspberry ketone on hypothalamic inflammation and its mechanism. Mouse microglia cells (BV2 cells) were cultured in vitro with palmitic acid (100 μM) to induce inflammation model and then incubated with raspberry ketone (5, 20, 50 μM) alone or raspberry ketone (50 μM) and the specific inhibitor of uncoupling protein 2 (UCP2), genipin (10 μM), to test the role of UCP2 in raspberry ketone regulatory of inflammation. Meanwhile, C57BL/6J mice were fed a high-fat diet containing raspberry ketone (0.2%, wt/wt) for 16 wk or 7 d to observe the effects of raspberry ketone on the body weights and hypothalamic inflammation of mice. The expression levels of inflammatory factors, including interleukin-6 (IL-6), interleukin-1beta (IL-1β) and tumour necrosis factor alpha (TNF-α), were detected using RT-qPCR, Elisa, and Western blotting, respectively. At the cellular level, raspberry ketone reduced the content of inflammatory factors in BV2 cells and in the cell culture medium. Genipin inhibited the anti-inflammatory effect of raspberry ketone on BV2 cells. At the animal level, after 16 wk of feeding, raspberry ketone-containing diets significantly reduced the body weight of mice, but had no significant effect on the mRNA expression level of hypothalamic inflammatory factors. On the other hand, 7 d of raspberry ketone gavage significantly reduced mRNA and protein expression of hypothalamic inflammatory factors. The results of this study suggest that raspberry ketone could regulate high-fat diet-induced obesity in mice, and the specific mechanism may be to inhibit hypothalamic inflammation in mice by regulating UCP2 gene expression.
Collapse
Affiliation(s)
- Zhao Yao
- College of Health Industry, Sichuan Tourism University
| | - Zhenhua Zhu
- Key Laboratory of Sichuan Cuisine Artificial Intelligence, Sichuan Tourism University
- Cuisine Science Key Laboratory of Sichuan Province, Sichuan Tourism University
| | - Xingyou Chen
- Key Laboratory of Sichuan Cuisine Artificial Intelligence, Sichuan Tourism University
| | - Xiaoping Li
- Key Laboratory of Sichuan Cuisine Artificial Intelligence, Sichuan Tourism University
- Cuisine Science Key Laboratory of Sichuan Province, Sichuan Tourism University
- College of Culinary, Sichuan Tourism University
- State Key Laboratory of Food Science and Resource, Nanchang University
| |
Collapse
|
|
7
|
Roy S, Das A, Bairagi A, Das D, Jha A, Srivastava AK, Chatterjee N. Mitochondria act as a key regulatory factor in cancer progression: Current concepts on mutations, mitochondrial dynamics, and therapeutic approach. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2024; 793:108490. [PMID: 38460864 DOI: 10.1016/j.mrrev.2024.108490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 02/12/2024] [Accepted: 02/22/2024] [Indexed: 03/11/2024]
Abstract
The diversified impacts of mitochondrial function vs. dysfunction have been observed in almost all disease conditions including cancers. Mitochondria play crucial roles in cellular homeostasis and integrity, however, mitochondrial dysfunctions influenced by alterations in the mtDNA can disrupt cellular balance. Many external stimuli or cellular defects that cause cellular integrity abnormalities, also impact mitochondrial functions. Imbalances in mitochondrial activity can initiate and lead to accumulations of genetic mutations and can promote the processes of tumorigenesis, progression, and survival. This comprehensive review summarizes epigenetic and genetic alterations that affect the functionality of the mitochondria, with considerations of cellular metabolism, and as influenced by ethnicity. We have also reviewed recent insights regarding mitochondrial dynamics, miRNAs, exosomes that play pivotal roles in cancer promotion, and the impact of mitochondrial dynamics on immune cell mechanisms. The review also summarizes recent therapeutic approaches targeting mitochondria in anti-cancer treatment strategies.
Collapse
Affiliation(s)
- Sraddhya Roy
- Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata 700026, India
| | - Ananya Das
- Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata 700026, India
| | - Aparajita Bairagi
- Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata 700026, India
| | - Debangshi Das
- Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata 700026, India
| | - Ashna Jha
- Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata 700026, India
| | - Amit Kumar Srivastava
- CSIR-IICB Translational Research Unit Of Excellence, CN-6, Salt Lake, Sector - V, Kolkata 700091, India
| | - Nabanita Chatterjee
- Chittaranjan National Cancer Institute, 37 S. P. Mukherjee Road, Kolkata 700026, India.
| |
Collapse
|
|
8
|
Musillo C, Creutzberg KC, Collacchi B, Ajmone-Cat MA, De Simone R, Lepre M, Amrein I, Riva MA, Berry A, Cirulli F. Bdnf-Nrf-2 crosstalk and emotional behavior are disrupted in a sex-dependent fashion in adolescent mice exposed to maternal stress or maternal obesity. Transl Psychiatry 2023; 13:399. [PMID: 38105264 PMCID: PMC10725882 DOI: 10.1038/s41398-023-02701-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 11/28/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023] Open
Abstract
Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic-pituitary-adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal. Prenatal administration of the antioxidant N-acetyl-cysteine (NAC) was used as a strategy to protect fetal neurodevelopment from the negative effects of PNS and mHFD. Our findings show that these two stressors produce overlapping effects, reducing brain anti-oxidant defenses (Nrf-2) and leading to sex-dependent impairments of hippocampal Bdnf expression and alterations of the emotional behavior and HPA axis functionality. Prenatal NAC administration, by restoring the redox balance, was able to exert long-term protective effects on brain development, suggesting that the modulation of redox pathways might be an effective strategy to target common shared mechanisms between different adverse prenatal conditions.
Collapse
Affiliation(s)
- Chiara Musillo
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
- Ph.D. Program in Behavioral Neuroscience, Department of Psychology, Sapienza University of Rome, 00185, Rome, Italy
| | - Kerstin C Creutzberg
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Barbara Collacchi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Maria Antonietta Ajmone-Cat
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Roberta De Simone
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Marcello Lepre
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Irmgard Amrein
- Functional Neuroanatomy, Institute of Anatomy, University of Zürich, Zurich, Switzerland
| | - Marco A Riva
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Alessandra Berry
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| | - Francesca Cirulli
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
| |
Collapse
|
|
9
|
Ruck L, Wiegand S, Kühnen P. Relevance and consequence of chronic inflammation for obesity development. Mol Cell Pediatr 2023; 10:16. [PMID: 37957462 PMCID: PMC10643747 DOI: 10.1186/s40348-023-00170-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Increasing prevalence of morbid obesity accompanied by comorbidities like type 2 diabetes mellitus (T2DM) led to a demand for improving therapeutic strategies and pharmacological intervention options. Apart from genetics, inflammation processes have been hypothesized to be of importance for the development of obesity and related aspects like insulin resistance. MAIN TEXT Within this review, we provide an overview of the intricate interplay between chronic inflammation of the adipose tissue and the hypothalamus and the development of obesity. Further understanding of this relationship might improve the understanding of the underlying mechanism and may be of relevance for the establishment of new treatment strategies.
Collapse
Affiliation(s)
- Lisa Ruck
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany.
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Charitéplatz 1, 10117, Berlin, Germany.
| | - Susanna Wiegand
- Abteilung Interdisziplinär, Sozial-Pädiatrisches Zentrum, Charité Universitätsmedizin, Berlin, Germany
| | - Peter Kühnen
- Klinik Für Pädiatrische Endokrinologie und Diabetologie, Charité Universitätsmedizin, Berlin, Germany
| |
Collapse
|
|
10
|
Ragupathy H, Vukku M, Barodia SK. Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration. Int J Mol Sci 2023; 24:14421. [PMID: 37833867 PMCID: PMC10572699 DOI: 10.3390/ijms241914421] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/21/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which is a well-accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of the neuronal population due to increased oxidative stress leads to neurodegenerative diseases, mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is a key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitute a significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decide the fate of overall brain health; therefore, it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable the diversity and highly synchronized connecting property of non-neuronal cells are in keeping the neurons healthy to control neurodegeneration.
Collapse
Affiliation(s)
| | - Manasvi Vukku
- Centre for Brain Research, Indian Institute of Science, Bengaluru 560012, India
| | | |
Collapse
|
|
11
|
Kagawa Y, Low YL, Pyun J, Doglione U, Short JL, Pan Y, Nicolazzo JA. Fatty Acid-Binding Protein 4 is Essential for the Inflammatory and Metabolic Response of Microglia to Lipopolysaccharide. J Neuroimmune Pharmacol 2023; 18:448-461. [PMID: 37555918 PMCID: PMC10577108 DOI: 10.1007/s11481-023-10079-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 07/10/2023] [Indexed: 08/10/2023]
Abstract
Prolonged activation of microglia leads to excessive release of proinflammatory mediators, which are detrimental to brain health. Therefore, there are significant efforts to identify pathways mediating microglial activation. Recent studies have demonstrated that fatty acid-binding protein 4 (FABP4), a lipid binding protein, is a critical player in macrophage-mediated inflammation. Given that we have previously identified FABP4 in microglia, the aim of this study was to assess whether FABP4 activity contributed to inflammation, metabolism and immune function (i.e. immunometabolism) in immortalised mouse microglia (BV-2 cells) using the proinflammatory stimulus lipopolysaccharide (LPS) to induce general microglial activation. Microglial FABP4 expression was significantly increased following exposure to LPS, an outcome associated with a significant increase in microglial proliferation rate. LPS-stimulated BV-2 microglia demonstrated a significant increase in the production of reactive oxygen species (ROS) and tumour necrosis factor-alpha (TNF-α), phosphorylation of c-Jun N-terminal kinase (JNK), increased expression of Toll-like receptor 4 (TLR4), and reduced expression of uncoupling protein 2 (UCP2), all of which were reversed following FABP4 genetic silencing and chemical inhibition with BMS309403. The oxidation rate of 3H-oleic acid and microglial uptake of 3H-2-deoxy-D-glucose were modulated with LPS activation, processes which were restored with genetic and chemical inhibition of FABP4. This is the first study to report on the critical role of FABP4 in mediating the deleterious effects of LPS on microglial immunometabolism, suggesting that FABP4 may present as a novel therapeutic target to alleviate microglia-mediated neuroinflammation, a commonly reported factor in multiple neurodegenerative diseases.
Collapse
Affiliation(s)
- Yoshiteru Kagawa
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 3052, Parkville, VIC, Australia
- Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Yi Ling Low
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 3052, Parkville, VIC, Australia
| | - Jae Pyun
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 3052, Parkville, VIC, Australia
| | - Umberto Doglione
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 3052, Parkville, VIC, Australia
| | - Jennifer L Short
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 3052, Parkville, VIC, Australia
| | - Yijun Pan
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 3052, Parkville, VIC, Australia.
| | - Joseph A Nicolazzo
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 3052, Parkville, VIC, Australia.
| |
Collapse
|
|
12
|
Sousa T, Moreira PI, Cardoso S. Current Advances in Mitochondrial Targeted Interventions in Alzheimer's Disease. Biomedicines 2023; 11:2331. [PMID: 37760774 PMCID: PMC10525414 DOI: 10.3390/biomedicines11092331] [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: 07/11/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023] Open
Abstract
Alzheimer's disease is the most prevalent neurodegenerative disorder and affects the lives not only of those who are diagnosed but also of their caregivers. Despite the enormous social, economic and political burden, AD remains a disease without an effective treatment and with several failed attempts to modify the disease course. The fact that AD clinical diagnosis is most often performed at a stage at which the underlying pathological events are in an advanced and conceivably irremediable state strongly hampers treatment attempts. This raises the awareness of the need to identify and characterize the early brain changes in AD, in order to identify possible novel therapeutic targets to circumvent AD's cascade of events. One of the most auspicious targets is mitochondria, powerful organelles found in nearly all cells of the body. A vast body of literature has shown that mitochondria from AD patients and model organisms of the disease differ from their non-AD counterparts. In view of this evidence, preserving and/or restoring mitochondria's health and function can represent the primary means to achieve advances to tackle AD. In this review, we will briefly assess and summarize the previous and latest evidence of mitochondria dysfunction in AD. A particular focus will be given to the recent updates and advances in the strategy options aimed to target faulty mitochondria in AD.
Collapse
Affiliation(s)
- Tiago Sousa
- Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal;
| | - Paula I. Moreira
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-370 Coimbra, Portugal
| | - Susana Cardoso
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
- IIIUC—Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| |
Collapse
|
|
13
|
A lncRNA-encoded mitochondrial micropeptide exacerbates microglia-mediated neuroinflammation in retinal ischemia/reperfusion injury. Cell Death Dis 2023; 14:126. [PMID: 36792584 PMCID: PMC9932084 DOI: 10.1038/s41419-023-05617-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 01/20/2023] [Accepted: 01/25/2023] [Indexed: 02/17/2023]
Abstract
As a common pathology of many ocular disorders such as diabetic retinopathy and glaucoma, retinal ischemia/reperfusion (IR) triggers inflammation and microglia activation that lead to irreversible retinal damage. The detailed molecular mechanism underlying retinal IR injury, however, remains poorly understood at present. Here we report the bioinformatic identification of a lncRNA 1810058I24Rik (181-Rik) that was shown to encode a mitochondrion-located micropeptide Stmp1. Its deficiency in mice protected retinal ganglion cells from retinal IR injury by attenuating the activation of microglia and the Nlrp3 inflammasome pathway. Moreover, its genetic knockout in mice or knockdown in primary microglia promoted mitochondrial fusion, impaired mitochondrial membrane potential, and reactive oxygen species (ROS) production, diminished aerobic glycolysis, and ameliorated inflammation. It appears that 181-Rik may trigger the Nlrp3 inflammasome activation by controlling mitochondrial functions through inhibiting expression of the metabolic sensor uncoupling protein 2 (Ucp2) and activating expression of the Ca2+ sensors S100a8/a9. Together, our findings shed new light on the molecular pathogenesis of retinal IR injury and may provide a fresh therapeutic target for IR-associated neurodegenerative diseases.
Collapse
|
|
14
|
Stewart AN, Jones LAT, Gensel JC. Improving translatability of spinal cord injury research by including age as a demographic variable. Front Cell Neurosci 2022; 16:1017153. [PMID: 36467608 PMCID: PMC9714671 DOI: 10.3389/fncel.2022.1017153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/04/2022] [Indexed: 11/18/2022] Open
Abstract
Pre-clinical and clinical spinal cord injury (SCI) studies differ in study design, particularly in the demographic characteristics of the chosen population. In clinical study design, criteria such as such as motor scores, neurological level, and severity of injury are often key determinants for participant inclusion. Further, demographic variables in clinical trials often include individuals from a wide age range and typically include both sexes, albeit historically most cases of SCI occur in males. In contrast, pre-clinical SCI models predominately utilize young adult rodents and typically use only females. While it is often not feasible to power SCI clinical trials to test multi-variable designs such as contrasting different ages, recent pre-clinical findings in SCI animal models have emphasized the importance of considering age as a biological variable prior to human experiments. Emerging pre-clinical data have identified case examples of treatments that diverge in efficacy across different demographic variables and have elucidated several age-dependent effects in SCI. The extent to which these differing or diverging treatment responses manifest clinically can not only complicate statistical findings and trial interpretations but also may be predictive of worse outcomes in select clinical populations. This review highlights recent literature including age as a biological variable in pre-clinical studies and articulates the results with respect to implications for clinical trials. Based on emerging unpredictable treatment outcomes in older rodents, we argue for the importance of including age as a biological variable in pre-clinical animal models prior to clinical testing. We believe that careful analyses of how age interacts with SCI treatments and pathophysiology will help guide clinical trial design and may improve both the safety and outcomes of such important efforts.
Collapse
Affiliation(s)
- Andrew N. Stewart
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, United States,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Linda A. T. Jones
- Center for Outcomes and Measurement, Jefferson College of Rehabilitation Sciences, Thomas Jefferson University, Philadelphia, PA, United States
| | - John C. Gensel
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, United States,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States,*Correspondence: John C. Gensel,
| |
Collapse
|
|
15
|
Javanmehr N, Saleki K, Alijanizadeh P, Rezaei N. Microglia dynamics in aging-related neurobehavioral and neuroinflammatory diseases. J Neuroinflammation 2022; 19:273. [PMID: 36397116 PMCID: PMC9669544 DOI: 10.1186/s12974-022-02637-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 11/01/2022] [Indexed: 11/18/2022] Open
Abstract
Microglia represent the first line of immune feedback in the brain. Beyond immune surveillance, they are essential for maintaining brain homeostasis. Recent research has revealed the microglial cells' spatiotemporal heterogeneity based on their local and time-based functions in brain trauma or disease when homeostasis is disrupted. Distinct "microglial signatures" have been recorded in physiological states and brain injuries, with discrete or sometimes overlapping pro- and anti-inflammatory functions. Microglia are involved in the neurological repair processes, such as neurovascular unit restoration and synaptic plasticity, and manage the extent of the damage due to their phenotype switching. The versatility of cellular phenotypes beyond the classical M1/M2 classification, as well as the double-edge actions of microglia in neurodegeneration, indicate the need for further exploration of microglial cell dynamics and their contribution to neurodegenerative processes. This review discusses the homeostatic functions of different microglial subsets focusing on neuropathological conditions. Also, we address the feasibility of targeting microglia as a therapeutic strategy in neurodegenerative diseases.
Collapse
Affiliation(s)
- Nima Javanmehr
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
- USERN Office, Babol University of Medical Sciences, Babol, Iran
| | - Kiarash Saleki
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
- USERN Office, Babol University of Medical Sciences, Babol, Iran
| | - Parsa Alijanizadeh
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
- USERN Office, Babol University of Medical Sciences, Babol, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| |
Collapse
|
|
16
|
Smith AN, Shaughness M, Collier S, Hopkins D, Byrnes KR. Therapeutic targeting of microglia mediated oxidative stress after neurotrauma. Front Med (Lausanne) 2022; 9:1034692. [PMID: 36405593 PMCID: PMC9671221 DOI: 10.3389/fmed.2022.1034692] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/12/2022] [Indexed: 10/06/2023] Open
Abstract
Inflammation is a primary component of the central nervous system injury response. Traumatic brain and spinal cord injury are characterized by a pronounced microglial response to damage, including alterations in microglial morphology and increased production of reactive oxygen species (ROS). The acute activity of microglia may be beneficial to recovery, but continued inflammation and ROS production is deleterious to the health and function of other cells. Microglial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), mitochondria, and changes in iron levels are three of the most common sources of ROS. All three play a significant role in post-traumatic brain and spinal cord injury ROS production and the resultant oxidative stress. This review will evaluate the current state of therapeutics used to target these avenues of microglia-mediated oxidative stress after injury and suggest avenues for future research.
Collapse
Affiliation(s)
- Austin N. Smith
- Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Michael Shaughness
- Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Sean Collier
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Deanna Hopkins
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| | - Kimberly R. Byrnes
- Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
| |
Collapse
|
|
17
|
Uzunlulu G, Uzunlulu M, Gencer A, Özdoğru F, Seven S. Knowledge on Medical Waste Management Among Health Care Personnel: A Report from Turkey. CYPRUS JOURNAL OF MEDICAL SCIENCES 2022. [DOI: 10.4274/cjms.2020.1107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
|
|
18
|
Microglial FABP4-UCP2 Axis Modulates Neuroinflammation and Cognitive Decline in Obese Mice. Int J Mol Sci 2022; 23:ijms23084354. [PMID: 35457171 PMCID: PMC9032181 DOI: 10.3390/ijms23084354] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 01/22/2023] Open
Abstract
The microglial fatty-acid-binding protein 4-uncoupling protein 2 (FABP4-UCP2) axis is a key regulator of neuroinflammation in high-fat-diet (HFD)-fed animals, indicating a role for FABP4 in brain immune response. We hypothesized that the FABP4-UCP2 axis is involved in regulating diet-induced cognitive decline. We tested cognitive function in mice lacking microglial FABP4 (AKO mice). Fifteen-week-old male AKO and wild-type (WT) mice were maintained on 60% HFD or normal chow (NC) for 12 weeks. Body composition was measured using EchoMRI. Locomotor activity, working memory, and spatial memory were assessed using behavioral tests (open field, T-maze, and Barnes maze, respectively). Hippocampal microgliosis was assessed via immunohistochemical staining. An inflammatory cytokine panel was assayed using hippocampal tissue. Real-time RT-PCR was performed to measure microglial UCP2 mRNA expression. Our data support that loss of FABP4 prevents cognitive decline in vivo. HFD-fed WT mice exhibited impaired long- and short-term memory, in contrast with HFD-fed AKO mice. HFD-fed WT mice had an increase in hippocampal inflammatory cytokine expression (IFNγ, IL-1β, IL-5, IL-6, KC/GRO(CXCL1), IL-10, and TNFα) and microgliosis, and decreased microglial UCP2 expression. HFD-fed AKO mice had decreased hippocampal inflammatory cytokine expression and microgliosis and increased microglial UCP2 expression compared to HFD-fed WT mice. Collectively, our work supports the idea that the FABP4-UCP2 axis represents a potential therapeutic target in preventing diet-induced cognitive decline.
Collapse
|
|
19
|
Slater PG, Domínguez-Romero ME, Villarreal M, Eisner V, Larraín J. Mitochondrial function in spinal cord injury and regeneration. Cell Mol Life Sci 2022; 79:239. [PMID: 35416520 PMCID: PMC11072423 DOI: 10.1007/s00018-022-04261-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 12/21/2022]
Abstract
Many people around the world suffer from some form of paralysis caused by spinal cord injury (SCI), which has an impact on quality and life expectancy. The spinal cord is part of the central nervous system (CNS), which in mammals is unable to regenerate, and to date, there is a lack of full functional recovery therapies for SCI. These injuries start with a rapid and mechanical insult, followed by a secondary phase leading progressively to greater damage. This secondary phase can be potentially modifiable through targeted therapies. The growing literature, derived from mammalian and regenerative model studies, supports a leading role for mitochondria in every cellular response after SCI: mitochondrial dysfunction is the common event of different triggers leading to cell death, cellular metabolism regulates the immune response, mitochondrial number and localization correlate with axon regenerative capacity, while mitochondrial abundance and substrate utilization regulate neural stem progenitor cells self-renewal and differentiation. Herein, we present a comprehensive review of the cellular responses during the secondary phase of SCI, the mitochondrial contribution to each of them, as well as evidence of mitochondrial involvement in spinal cord regeneration, suggesting that a more in-depth study of mitochondrial function and regulation is needed to identify potential targets for SCI therapeutic intervention.
Collapse
Affiliation(s)
- Paula G Slater
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile.
| | - Miguel E Domínguez-Romero
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
| | - Maximiliano Villarreal
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
| | - Verónica Eisner
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
- Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
| | - Juan Larraín
- Center for Aging and Regeneration, Departamento de Biología Celular Y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331150, Santiago, Chile
| |
Collapse
|
|
20
|
Activation of UCP2 by anethole trithione suppresses neuroinflammation after intracerebral hemorrhage. Acta Pharmacol Sin 2022; 43:811-828. [PMID: 34183754 PMCID: PMC8976076 DOI: 10.1038/s41401-021-00698-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 05/14/2021] [Indexed: 02/06/2023]
Abstract
Intracerebral hemorrhage (ICH) is a devastating disease, in which neuroinflammation substantially contributes to brain injury. Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier family, which uncouples oxidative phosphorylation from ATP synthesis by facilitating proton leak across the mitochondrial inner membrane. UCP2 has been reported to modulate inflammation. In this study we investigated whether and how UCP2 modulated neuroinflammation through microglia/macrophages following ICH in vitro and in vivo. We used an in vitro neuroinflammation model in murine BV2 microglia to mimic microglial activation following ICH. ICH in vivo model was established in mice through collagenase infusion into the left striatum. ICH mice were treated with anetholetrithione (ADT, 50 mg· kg-1 ·d-1, ip) or the classical protonophoric uncoupler FCCP (injected into hemorrhagic striatum). We showed that the expression and mitochondrial location of microglial UCP2 were not changed in both in vitro and in vivo ICH models. Knockdown of UCP2 exacerbated neuroinflammation in BV2 microglia and mouse ICH models, suggesting that endogenous UCP2 inhibited neuroinflammation and therefore played a protective role following ICH. ADT enhanced mitochondrial ROS production thus inducing mitochondrial uncoupling and activating UCP2 in microglia. ADT robustly suppressed neuroinflammation, attenuated brain edema and improved neurological deficits following ICH, and these effects were countered by striatal knockdown of UCP2. ADT enhanced AMP-activated protein kinase (AMPK) activation in the hemorrhagic brain, which was abrogated by striatal knockdown of UCP2. Moreover, striatal knockdown of AMPK abolished the suppression of neuroinflammation by ADT following ICH. On the other hand, FCCP-induced mitochondrial uncoupling was independent of UCP2 in microglia; and striatal knockdown of UCP2 did not abrogate the suppression of neuroinflammation by FCCP in ICH mice. In conclusion, the uncoupling activity is essential for suppression of neuroinflammation by UCP2. We prove for the first time the concept that activators of endogenous UCP2 such as anetholetrithione are a new class of uncouplers with translational significance.
Collapse
|
|
21
|
Kumar R, T A, Singothu S, Singh SB, Bhandari V. Uncoupling proteins as a therapeutic target for the development of new era drugs against neurodegenerative disorder. Pharmacotherapy 2022; 147:112656. [DOI: 10.1016/j.biopha.2022.112656] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 12/21/2022]
|
|
22
|
Szalanczy AM, Key CCC, Woods LCS. Genetic variation in satiety signaling and hypothalamic inflammation: merging fields for the study of obesity. J Nutr Biochem 2022; 101:108928. [PMID: 34936921 PMCID: PMC8959400 DOI: 10.1016/j.jnutbio.2021.108928] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 11/08/2021] [Accepted: 12/01/2021] [Indexed: 02/07/2023]
Abstract
Although obesity has been a longstanding health crisis, the genetic architecture of the disease remains poorly understood. Genome-wide association studies have identified many genomic loci associated with obesity, with genes being enriched in the brain, particularly in the hypothalamus. This points to the role of the central nervous system (CNS) in predisposition to obesity, and we emphasize here several key genes along the satiety signaling pathway involved in genetic susceptibility. Interest has also risen regarding the chronic, low-grade obesity-associated inflammation, with a growing concern toward inflammation in the hypothalamus as a precursor to obesity. Recent studies have found that genetic variation in inflammatory genes play a role in obesity susceptibility, and we highlight here several key genes. Despite the interest in the genetic variants of these pathways individually, there is a lack of research that investigates the relationship between the two. Understanding the interplay between genetic variation in obesity genes enriched in the CNS and inflammation genes will advance our understanding of obesity etiology and heterogeneity, improve genetic risk prediction analyses, and highlight new drug targets for the treatment of obesity. Additionally, this increased knowledge will assist in physician's ability to develop personalized nutrition and medication strategies for combating the obesity epidemic. Though it often seems to present universally, obesity is a highly individual disease, and there remains a need in the field to develop methods to treat at the individual level.
Collapse
|
|
23
|
Chen Y, Li Y. Metabolic reprogramming and immunity in cancer. CANCER IMMUNOLOGY AND IMMUNOTHERAPY 2022:137-196. [DOI: 10.1016/b978-0-12-823397-9.00006-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
24
|
Mitochondrial Uncoupling Proteins (UCPs) as Key Modulators of ROS Homeostasis: A Crosstalk between Diabesity and Male Infertility? Antioxidants (Basel) 2021; 10:antiox10111746. [PMID: 34829617 PMCID: PMC8614977 DOI: 10.3390/antiox10111746] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022] Open
Abstract
Uncoupling proteins (UCPs) are transmembrane proteins members of the mitochondrial anion transporter family present in the mitochondrial inner membrane. Currently, six homologs have been identified (UCP1-6) in mammals, with ubiquitous tissue distribution and multiple physiological functions. UCPs are regulators of key events for cellular bioenergetic metabolism, such as membrane potential, metabolic efficiency, and energy dissipation also functioning as pivotal modulators of ROS production and general cellular redox state. UCPs can act as proton channels, leading to proton re-entry the mitochondrial matrix from the intermembrane space and thus collapsing the proton gradient and decreasing the membrane potential. Each homolog exhibits its specific functions, from thermogenesis to regulation of ROS production. The expression and function of UCPs are intimately linked to diabesity, with their dysregulation/dysfunction not only associated to diabesity onset, but also by exacerbating oxidative stress-related damage. Male infertility is one of the most overlooked diabesity-related comorbidities, where high oxidative stress takes a major role. In this review, we discuss in detail the expression and function of the different UCP homologs. In addition, the role of UCPs as key regulators of ROS production and redox homeostasis, as well as their influence on the pathophysiology of diabesity and potential role on diabesity-induced male infertility is debated.
Collapse
|
|
25
|
Li YQ, Chen Y, Jiang SQ, Shi YY, Jiang XL, Wu SS, Zhou P, Wang HY, Li P, Li F. An Inhibitor of NF-κB and an Agonist of AMPK: Network Prediction and Multi-Omics Integration to Derive Signaling Pathways for Acteoside Against Alzheimer's Disease. Front Cell Dev Biol 2021; 9:652310. [PMID: 34350171 PMCID: PMC8327963 DOI: 10.3389/fcell.2021.652310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 06/23/2021] [Indexed: 01/26/2023] Open
Abstract
Alzheimer’s disease (AD) is the most frequent type of dementia. Acteoside (ACT) is a compound isolated from Cistanche tubulosa, which possesses excellent neuroprotective properties. However, the underlying mechanism of ACT in regulating microglia polarization remains ill-defined. Therefore, a computational network model was established to identify the driving targets of ACT and predict its mechanism by integrating multiple available databases. The AlCl3-induced AD model in zebrafish larvae was successfully constituted to demonstrate the therapeutic efficacy of ACT. Subsequently, LPS-induced BV-2 cells uncovered the positive role of ACT in M1/M2 polarization. The NF-κB and AMPK pathways were further confirmed by transcriptomic analysis, metabolomics analysis, molecular biology techniques, and molecular docking. The research provided an infusive mechanism of ACT and revealed the connection between metabolism and microglia polarization from the perspective of mitochondrial function. More importantly, it provided a systematic and comprehensive approach for the discovery of drug targets, including the changes in genes, metabolites, and proteins.
Collapse
Affiliation(s)
- Ying-Qi Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Yi Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Si-Qi Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Yuan-Yuan Shi
- College of Pharmacy, Xinjiang Medical University, Urumqi, China
| | - Xiao-Li Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Shan-Shan Wu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Ping Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Hui-Ying Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Fei Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,College of Pharmacy, Xinjiang Medical University, Urumqi, China
| |
Collapse
|
|
26
|
Gautier EL, Askia H, Murcy F, Yvan-Charvet L. Macrophage ontogeny and functional diversity in cardiometabolic diseases. Semin Cell Dev Biol 2021; 119:119-129. [PMID: 34229949 DOI: 10.1016/j.semcdb.2021.06.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 06/01/2021] [Accepted: 06/28/2021] [Indexed: 12/24/2022]
Abstract
Macrophages are the dominant immune cell types in the adipose tissue, the liver or the aortic wall and they were originally believed to mainly derived from monocytes to fuel tissue inflammation in cardiometabolic diseases. However, over the last decade the identification of tissue resident macrophages (trMacs) from embryonic origin in these metabolic tissues has provided a breakthrough in the field forcing to better comprehend macrophage diversity during pathological states. Infiltrated monocyte-derived macrophages (moMacs), similar to trMacs, adapt to the local metabolic environment that eventually shapes their functions. In this review, we will summarize the emerging versatility of macrophages in cardiometabolic diseases with a focus in the control of adipose tissue, liver and large vessels homeostasis.
Collapse
Affiliation(s)
- Emmanuel L Gautier
- Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-S 1166, Sorbonne Université, 75013 Paris, France.
| | - Haoussa Askia
- Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-S 1166, Sorbonne Université, 75013 Paris, France
| | - Florent Murcy
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Laurent Yvan-Charvet
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France.
| |
Collapse
|
|
27
|
Dang CP, Issara-Amphorn J, Charoensappakit A, Udompornpitak K, Bhunyakarnjanarat T, Saisorn W, Sae-Khow K, Leelahavanichkul A. BAM15, a Mitochondrial Uncoupling Agent, Attenuates Inflammation in the LPS Injection Mouse Model: An Adjunctive Anti-Inflammation on Macrophages and Hepatocytes. J Innate Immun 2021; 13:359-375. [PMID: 34062536 PMCID: PMC8613553 DOI: 10.1159/000516348] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/30/2021] [Indexed: 11/19/2022] Open
Abstract
Controlof immune responses through the immunometabolism interference is interesting for sepsis treatment. Then, expression of immunometabolism-associated genes and BAM15, a mitochondrial uncoupling agent, was explored in a proinflammatory model using lipopolysaccharide (LPS) injection. Accordingly, the decreased expression of mitochondrial uncoupling proteins was demonstrated by transcriptomic analysis on metabolism-associated genes in macrophages (RAW246.7) and by polymerase chain reaction in LPS-stimulated RAW246.7 and hepatocytes (Hepa 1-6). Pretreatment with BAM15 at 24 h prior to LPS in macrophages attenuated supernatant inflammatory cytokines (IL-6, TNF-α, and IL-10), downregulated genes of proinflammatory M1 polarization (iNOS and IL-1β), upregulated anti-inflammatory M2 polarization (Arg1 and FIZZ), and decreased cell energy status (extracellular flux analysis and ATP production). Likewise, BAM15 decreased expression of proinflammatory genes (IL-6, TNF-α, IL-10, and iNOS) and reduced cell energy in hepatocytes. In LPS-administered mice, BAM15 attenuated serum cytokines, organ injury (liver enzymes and serum creatinine), and tissue cytokines (livers and kidneys), in part, through the enhanced phosphorylated αAMPK, a sensor of ATP depletion with anti-inflammatory property, in the liver, and reduced inflammatory monocytes/macrophages (Ly6C +ve, CD11b +ve) in the liver as detected by Western blot and flow cytometry, respectively. In conclusion, a proof of concept for inflammation attenuation of BAM15 through metabolic interference-induced anti-inflammation on macrophages and hepatocytes was demonstrated as a new strategy of anti-inflammation in sepsis.
Collapse
Affiliation(s)
- Cong Phi Dang
- Medical Microbiology, Interdisciplinary and International Program, Graduate School, Chulalongkorn University, Bangkok, Thailand,
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand,
| | | | - Awirut Charoensappakit
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kanyarat Udompornpitak
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Wilasinee Saisorn
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kritsanawan Sae-Khow
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Asada Leelahavanichkul
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Translational Research in Inflammation and Immunology Research Unit (TRIRU), Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
28
|
Pan X, Song Y, He M, Yan X, Huang C, Li J, Dong W, Cheng J, Jia J. Mitochondrial Uncouplers Confer Protection by Activating AMP-Activated Protein Kinase to Inhibit Neuroinflammation Following Intracerebral Hemorrhage. Biol Pharm Bull 2021; 43:1210-1219. [PMID: 32741941 DOI: 10.1248/bpb.b20-00108] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Intracerebral hemorrhage (ICH) is a disease with high disability and mortality rates. Currently, the efficacy of therapies available for ICH is limited. Microglia-mediated neuroinflammation substantially exacerbates brain damage following ICH. Here, we investigated whether mitochondrial uncouplers conferred protection by suppressing neuroinflammation following ICH. To mimic ICH-induced neuroinflammation in vitro, we treated microglia with red blood cell (RBC) lysate. RBC lysate enhanced the expression of pro-inflammatory cytokines in microglia. A clinically used uncoupler, niclosamide (Nic), reduced the RBC lysate-induced expression of pro-inflammatory cytokines in microglia. Moreover, Nic ameliorated brain edema, decreased neuroinflammation, and improved neurological deficits in a well-established mouse model of ICH. Like niclosamide, the structurally unrelated uncoupler carbonyl cyanide p-triflouromethoxyphenylhydrazone (FCCP) reduced brain edema, decreased neuroinflammation, and improved neurological deficits following ICH. It has been reported that mitochondrial uncouplers activate AMP-activated protein kinase (AMPK). Mechanistically, Nic enhanced AMPK activation following ICH, and AMPK knockdown abolished the beneficial effects of Nic following ICH. In conclusion, mitochondrial uncouplers conferred protection by activating AMPK to inhibit microglial neuroinflammation following ICH.
Collapse
Affiliation(s)
- Xiaofan Pan
- Department of Neurology, The First Affiliated Hospital of Soochow University.,Department of Neurology, Wuxi Xishan People's Hospital
| | - Yanmei Song
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University
| | - Meijun He
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University
| | - Xiaoling Yan
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University
| | - Caiyun Huang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University
| | - Jie Li
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University
| | - Wanli Dong
- Department of Neurology, The First Affiliated Hospital of Soochow University
| | - Jian Cheng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University
| | - Jia Jia
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University
| |
Collapse
|
|
29
|
Folick A, Koliwad SK, Valdearcos M. Microglial Lipid Biology in the Hypothalamic Regulation of Metabolic Homeostasis. Front Endocrinol (Lausanne) 2021; 12:668396. [PMID: 34122343 PMCID: PMC8191416 DOI: 10.3389/fendo.2021.668396] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/05/2021] [Indexed: 12/18/2022] Open
Abstract
In mammals, myeloid cells help maintain the homeostasis of peripheral metabolic tissues, and their immunologic dysregulation contributes to the progression of obesity and associated metabolic disease. There is accumulating evidence that innate immune cells also serve as functional regulators within the mediobasal hypothalamus (MBH), a critical brain region controlling both energy and glucose homeostasis. Specifically, microglia, the resident parenchymal myeloid cells of the CNS, play important roles in brain physiology and pathology. Recent studies have revealed an expanding array of microglial functions beyond their established roles as immune sentinels, including roles in brain development, circuit refinement, and synaptic organization. We showed that microglia modulate MBH function by transmitting information resulting from excess nutrient consumption. For instance, microglia can sense the excessive consumption of saturated fats and instruct neurons within the MBH accordingly, leading to responsive alterations in energy balance. Interestingly, the recent emergence of high-resolution single-cell techniques has enabled specific microglial populations and phenotypes to be profiled in unprecedented detail. Such techniques have highlighted specific subsets of microglia notable for their capacity to regulate the expression of lipid metabolic genes, including lipoprotein lipase (LPL), apolipoprotein E (APOE) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). The discovery of this transcriptional signature highlights microglial lipid metabolism as a determinant of brain health and disease pathogenesis, with intriguing implications for the treatment of brain disorders and potentially metabolic disease. Here we review our current understanding of how changes in microglial lipid metabolism could influence the hypothalamic control of systemic metabolism.
Collapse
Affiliation(s)
- Andrew Folick
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Suneil K. Koliwad
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Martin Valdearcos
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
| |
Collapse
|
|
30
|
Candida Administration in Bilateral Nephrectomy Mice Elevates Serum (1→3)-β-D-glucan That Enhances Systemic Inflammation Through Energy Augmentation in Macrophages. Int J Mol Sci 2021; 22:ijms22095031. [PMID: 34068595 PMCID: PMC8126065 DOI: 10.3390/ijms22095031] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/18/2021] [Accepted: 04/29/2021] [Indexed: 12/15/2022] Open
Abstract
Systemic inflammation, from gut translocation of organismal molecules, might worsen uremic complications in acute kidney injury (AKI). The monitoring of gut permeability integrity and/or organismal molecules in AKI might be clinically beneficial. Due to the less prominence of Candida albicans in human intestine compared with mouse gut, C. albicans were orally administered in bilateral nephrectomy (BiN) mice. Gut dysbiosis, using microbiome analysis, and gut permeability defect (gut leakage), which was determined by fluorescein isothiocyanate-dextran and intestinal tight-junction immunofluorescent staining, in mice with BiN-Candida was more severe than BiN without Candida. Additionally, profound gut leakage in BiN-Candida also resulted in gut translocation of lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG), the organismal components from gut contents, that induced more severe systemic inflammation than BiN without Candida. The co-presentation of LPS and BG in mouse serum enhanced inflammatory responses. As such, LPS with Whole Glucan Particle (WGP, a representative BG) induced more severe macrophage responses than LPS alone as determined by supernatant cytokines and gene expression of downstream signals (NFκB, Malt-1 and Syk). Meanwhile, WGP alone did not induced the responses. In parallel, WGP (with or without LPS), but not LPS alone, accelerated macrophage ATP production (extracellular flux analysis) through the upregulation of genes in mitochondria and glycolysis pathway (using RNA sequencing analysis), without the induction of cell activities. These data indicated a WGP pre-conditioning effect on cell energy augmentation. In conclusion, Candida in BiN mice accelerated gut translocation of BG that augmented cell energy status and enhanced pro-inflammatory macrophage responses. Hence, gut fungi and BG were associated with the enhanced systemic inflammation in acute uremia.
Collapse
|
|
31
|
Maher P. Investigations into the Role of Metabolism in the Inflammatory Response of BV2 Microglial Cells. Antioxidants (Basel) 2021; 10:109. [PMID: 33466581 PMCID: PMC7828726 DOI: 10.3390/antiox10010109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 01/16/2023] Open
Abstract
Although the hallmarks of Alzheimer's disease (AD) are amyloid beta plaques and neurofibrillary tangles, there is growing evidence that neuroinflammation, mitochondrial dysfunction and oxidative stress play important roles in disease development and progression. A major risk factor for the development of AD is diabetes, which is also characterized by oxidative stress and mitochondrial dysfunction along with chronic, low-grade inflammation. Increasing evidence indicates that in immune cells, the induction of a pro-inflammatory phenotype is associated with a shift from oxidative phosphorylation (OXPHOS) to glycolysis. However, whether hyperglycemia also contributes to this shift is not clear. Several different approaches including culturing BV2 microglial cells in different carbon sources, using enzyme inhibitors and knocking down key pathway elements were used in conjunction with bacterial lipopolysaccharide (LPS) activation to address this question. The results indicate that while high glucose favors NO production, pro-inflammatory cytokine production is highest in the presence of carbon sources that drive OXPHOS. In addition, among the carbon sources that drive OXPHOS, glutamine is a very potent inducer of IL6 production. This effect is dampened in the presence of glucose. Together, these results may provide new prospects for the therapeutic manipulation of neuroinflammation in the context of diabetes and AD.
Collapse
Affiliation(s)
- Pamela Maher
- Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| |
Collapse
|
|
32
|
Hass DT, Barnstable CJ. Uncoupling proteins in the mitochondrial defense against oxidative stress. Prog Retin Eye Res 2021; 83:100941. [PMID: 33422637 DOI: 10.1016/j.preteyeres.2021.100941] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/28/2020] [Accepted: 01/03/2021] [Indexed: 02/06/2023]
Abstract
Oxidative stress is a major component of most major retinal diseases. Many extrinsic anti-oxidative strategies have been insufficient at counteracting one of the predominant intrinsic sources of reactive oxygen species (ROS), mitochondria. The proton gradient across the inner mitochondrial membrane is a key driving force for mitochondrial ROS production, and this gradient can be modulated by members of the mitochondrial uncoupling protein (UCP) family. Of the UCPs, UCP2 shows a widespread distribution and has been shown to uncouple oxidative phosphorylation, with concomitant decreases in ROS production. Genetic studies using transgenic and knockout mice have documented the ability of increased UCP2 activity to provide neuroprotection in models of a number of diseases, including retinal diseases, indicating that it is a strong candidate for a therapeutic target. Molecular studies have identified the structural mechanism of action of UCP2 and have detailed the ways in which its expression and activity can be controlled at the transcriptional, translational and posttranslational levels. These studies suggest a number of ways in control of UCP2 expression and activity can be used therapeutically for both acute and chronic conditions. The development of such therapeutic approaches will greatly increase the tools available to combat a broad range of serious retinal diseases.
Collapse
Affiliation(s)
- Daniel T Hass
- Department of Biochemistry, The University of Washington, Seattle, WA, 98109, USA
| | - Colin J Barnstable
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA.
| |
Collapse
|
|
33
|
Morris G, Walker AJ, Walder K, Berk M, Marx W, Carvalho AF, Maes M, Puri BK. Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry. Mol Neurobiol 2021; 58:2158-2182. [PMID: 33411248 DOI: 10.1007/s12035-020-02212-w] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by NFE2L2. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of N-acetylcysteine, coenzyme Q10 and melatonin is accompanied by increased Nrf2 activity. N-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q10, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.
Collapse
Affiliation(s)
- G Morris
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - A J Walker
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - K Walder
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - M Berk
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.,CMMR Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia.,Orygen, The National Centre of Excellence in Youth Mental Health, The Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - W Marx
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - A F Carvalho
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.,Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada
| | - M Maes
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Barwon Health, School of Medicine, Deakin University, Geelong, VIC, Australia.,Department of Psychiatry, Chulalongkorn University, Bangkok, Thailand
| | | |
Collapse
|
|
34
|
Toney AM, Albusharif M, Works D, Polenz L, Schlange S, Chaidez V, Ramer-Tait AE, Chung S. Differential Effects of Whole Red Raspberry Polyphenols and Their Gut Metabolite Urolithin A on Neuroinflammation in BV-2 Microglia. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 18:ijerph18010068. [PMID: 33374120 PMCID: PMC7795536 DOI: 10.3390/ijerph18010068] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/18/2020] [Accepted: 12/20/2020] [Indexed: 12/14/2022]
Abstract
Whole red raspberry polyphenols (RRW), including ellagic acid, and their gut-derived metabolite, urolithin A (UroA), attenuate inflammation and confer health benefits. Although results from recent studies indicate that polyphenols and UroA also provide neuroprotective effects, these compounds differ in their bioavailability and may, therefore, have unique effects on limiting neuroinflammation. Accordingly, we aimed to compare the neuroprotective effects of RRW and UroA on BV-2 microglia under both 3 h and 12 and 24 h inflammatory conditions. In inflammation induced by lipopolysaccharide (LPS) and ATP stimulation after 3 h, RRW and UroA suppressed pro-inflammatory cytokine gene expression and regulated the JNK/c-Jun signaling pathway. UroA also reduced inducible nitric oxide synthase gene expression and promoted M2 microglial polarization. During inflammatory conditions induced by either 12 or 24 h stimulation with LPS, UroA-but not RRW-dampened pro-inflammatory cytokine gene expression and suppressed JNK/c-Jun signaling. Taken together, these results demonstrate that RRW and its gut-derived metabolite UroA differentially regulate neuroprotective responses in microglia during 3 h versus 12 and 24 h inflammatory conditions.
Collapse
Affiliation(s)
- Ashley Mulcahy Toney
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; (A.M.T.); (D.W.); (L.P.); (S.S.); (V.C.)
| | - Mahaa Albusharif
- Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, NE 68588, USA; (M.A.); (A.E.R.-T.)
| | - Duncan Works
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; (A.M.T.); (D.W.); (L.P.); (S.S.); (V.C.)
- Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, NE 68588, USA; (M.A.); (A.E.R.-T.)
| | - Luke Polenz
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; (A.M.T.); (D.W.); (L.P.); (S.S.); (V.C.)
| | - Stacie Schlange
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; (A.M.T.); (D.W.); (L.P.); (S.S.); (V.C.)
| | - Virginia Chaidez
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; (A.M.T.); (D.W.); (L.P.); (S.S.); (V.C.)
| | - Amanda E. Ramer-Tait
- Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, NE 68588, USA; (M.A.); (A.E.R.-T.)
- Nebraska Food for Health Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Soonkyu Chung
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; (A.M.T.); (D.W.); (L.P.); (S.S.); (V.C.)
- Department of Nutrition, University of Massachusetts-Amherst, Amherst, MA 01003, USA
- Correspondence:
| |
Collapse
|
|
35
|
Dumont A, Lee M, Barouillet T, Murphy A, Yvan-Charvet L. Mitochondria orchestrate macrophage effector functions in atherosclerosis. Mol Aspects Med 2020; 77:100922. [PMID: 33162108 DOI: 10.1016/j.mam.2020.100922] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/28/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022]
Abstract
Macrophages are pivotal in the initiation and development of atherosclerotic cardiovascular diseases. Recent studies have reinforced the importance of mitochondria in metabolic and signaling pathways to maintain macrophage effector functions. In this review, we discuss the past and emerging roles of macrophage mitochondria metabolic diversity in atherosclerosis and the potential avenue as biomarker. Beyond metabolic functions, mitochondria are also a signaling platform integrating epigenetic, redox, efferocytic and apoptotic regulations, which are exquisitely linked to their dynamics. Indeed, mitochondria functions depend on their density and shape perpetually controlled by mitochondria fusion/fission and biogenesis/mitophagy balances. Mitochondria can also communicate with other organelles such as the endoplasmic reticulum through mitochondria-associated membrane (MAM) or be secreted for paracrine actions. All these functions are perturbed in macrophages from mouse or human atherosclerotic plaques. A better understanding and integration of how these metabolic and signaling processes are integrated and dictate macrophage effector functions in atherosclerosis may ultimately help the development of novel therapeutic approaches.
Collapse
Affiliation(s)
- Adélie Dumont
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204, Nice, France
| | - ManKS Lee
- Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia; Department of Immunology, Monash University, Melbourne, Victoria, 3165, Australia
| | - Thibault Barouillet
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204, Nice, France
| | - Andrew Murphy
- Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia; Department of Immunology, Monash University, Melbourne, Victoria, 3165, Australia
| | - Laurent Yvan-Charvet
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204, Nice, France.
| |
Collapse
|
|
36
|
Jia J, Wang Z, Zhang M, Huang C, Song Y, Xu F, Zhang J, Li J, He M, Li Y, Ao G, Hong C, Cao Y, Chin YE, Hua ZC, Cheng J. SQR mediates therapeutic effects of H 2S by targeting mitochondrial electron transport to induce mitochondrial uncoupling. SCIENCE ADVANCES 2020; 6:eaaz5752. [PMID: 32923620 PMCID: PMC7449675 DOI: 10.1126/sciadv.aaz5752] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 07/10/2020] [Indexed: 06/11/2023]
Abstract
Hydrogen sulfide (H2S) is a gasotransmitter and a potential therapeutic agent. However, molecular targets relevant to its therapeutic actions remain enigmatic. Sulfide-quinone oxidoreductase (SQR) irreversibly oxidizes H2S. Therefore, SQR is assumed to inhibit H2S signaling. We now report that SQR-mediated oxidation of H2S drives reverse electron transport (RET) at mitochondrial complex I, which, in turn, repurposes mitochondrial function to superoxide production. Unexpectedly, complex I RET, a process dependent on high mitochondrial membrane potential, induces superoxide-dependent mitochondrial uncoupling and downstream activation of adenosine monophosphate-activated protein kinase (AMPK). SQR-induced mitochondrial uncoupling is separated from the inhibition of mitochondrial complex IV by H2S. Moreover, deletion of SQR, complex I, or AMPK abolishes therapeutic effects of H2S following intracerebral hemorrhage. To conclude, SQR mediates H2S signaling and therapeutic effects by targeting mitochondrial electron transport to induce mitochondrial uncoupling. Moreover, SQR is a previously unrecognized target for developing non-protonophore uncouplers with broad clinical implications.
Collapse
Affiliation(s)
- Jia Jia
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Zichuang Wang
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Minjie Zhang
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Caiyun Huang
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Yanmei Song
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Fuyou Xu
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Jingyu Zhang
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Jie Li
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Meijun He
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Yuyao Li
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Guizhen Ao
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | | | - Yongjun Cao
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
| | - Y. Eugene Chin
- Institute of Biological and Medical Science, Soochow University, Suzhou, China
| | - Zi-chun Hua
- The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Jian Cheng
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
- Institute of Neuroscience, Soochow University, Suzhou, China
| |
Collapse
|
|
37
|
Harry GJ, Childers G, Giridharan S, Hernandes IL. An association between mitochondria and microglia effector function. What do we think we know? NEUROIMMUNOLOGY AND NEUROINFLAMMATION 2020; 7:150-165. [PMID: 32934971 PMCID: PMC7489447 DOI: 10.20517/2347-8659.2020.07] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
While resident innate immune cells of the central nervous system, the microglia, represent a cell population unique in origin, microenvironment, and longevity, they assume many properties displayed by peripheral macrophages. One prominent shared property is the ability to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS) upon activation by the pro-inflammatory stimuli lipopolysaccharide. This shift serves to meet specific cellular demands and allows for cell survival, similar to the Warburg effect demonstrated in cancer cells. In contrast, normal survelliance phenotype or stimulation to a non-proinflammatory phenotype relies primarily on OXPHOS and fatty acid oxidation. Thus, mitochondria appear to function as a pivotal signaling platform linking energy metabolism and macrophage polarization upon activation. These unique shifts in cell bioenergetics in response to different stimuli are essential for proper effector responses at sites of infection, inflammation, or injury. Here we present a summary of recent developments as to how these dynamics characterized in peripheral macrophages are displayed in microglia. The new insights provided by an increased understanding of metabolic reprogramming in macrophages may allow for translation to the CNS and a better understanding of microglia heterogeneity, regulation, and function.
Collapse
Affiliation(s)
- G Jean Harry
- National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 USA
| | - Gabrielle Childers
- National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 USA
- Current affiliation: Gabrielle Childers, University of Alabama, Birmingham, AL
| | - Sahana Giridharan
- National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 USA
- Giridharan, Duke University, Durham, NC
| | - Irisyunuel Lopez Hernandes
- National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 USA
| |
Collapse
|
|
38
|
Morris G, Puri BK, Maes M, Olive L, Berk M, Carvalho AF. The role of microglia in neuroprogressive disorders: mechanisms and possible neurotherapeutic effects of induced ketosis. Prog Neuropsychopharmacol Biol Psychiatry 2020; 99:109858. [PMID: 31923453 DOI: 10.1016/j.pnpbp.2020.109858] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 01/03/2020] [Accepted: 01/05/2020] [Indexed: 12/23/2022]
Abstract
A comprehensive review of molecular mechanisms involved in the promotion and maintenance of distinct microglia phenotypes is provided. The acquisition and perpetuation of predominantly pro-inflammatory microglial phenotypes have been implicated in the pathophysiology of several neuroprogressive diseases and is associated with reduced ATP production via oxidative phosphorylation, increased ATP generation by glycolysis, elevated oxidative and nitrosative stress and other metabolic, inflammatory and hormonal insults. Microglia can also adopt a predominantly anti-inflammatory phenotypes with neuroprotective properties. Strategies that promote and maintain a predominantly anti-inflammatory phenotype may hold promise as novel therapeutic opportunities for neuroprogressive illness. Induced ketosis may promote a transition towards predominantly anti-inflammatory microglial states/phenotypes by several mechanisms, including inhibition of glycolysis and increased NAD+ production; engagement of microglial GPR109A receptors; histone deacetylase inhibition; and elevated n-3 polyunsaturated fatty acids levels. Since microglia activation can now be assessed in vivo, these data provide a clear rationale for the design of transdiagnostic randomized controlled trials of the ketogenic diet and other ketosis-inducing strategies for neuroprogressive diseases, which may also provide mechanistic insights through the assessment of "target engagement".
Collapse
Affiliation(s)
- Gerwyn Morris
- Deakin University, IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Geelong, Victoria, Australia
| | | | - Michael Maes
- Deakin University, IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Geelong, Victoria, Australia
| | - Lisa Olive
- Deakin University, IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Geelong, Victoria, Australia
| | - Michael Berk
- Deakin University, IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Geelong, Victoria, Australia; Deakin University, CMMR Strategic Research Centre, School of Medicine, Geelong, Victoria, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, The Department of Psychiatry and the Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Andre F Carvalho
- Deakin University, IMPACT Strategic Research Centre, Barwon Health, School of Medicine, Geelong, Victoria, Australia; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
| |
Collapse
|
|
39
|
Devanney NA, Stewart AN, Gensel JC. Microglia and macrophage metabolism in CNS injury and disease: The role of immunometabolism in neurodegeneration and neurotrauma. Exp Neurol 2020; 329:113310. [PMID: 32289316 DOI: 10.1016/j.expneurol.2020.113310] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 03/25/2020] [Accepted: 04/10/2020] [Indexed: 12/12/2022]
Abstract
Innate immune responses, particularly activation of macrophages and microglia, are increasingly implicated in CNS disorders. It is now appreciated that the heterogeneity of functions adopted by these cells dictates neuropathophysiology. Research efforts to characterize the range of pro-inflammatory and anti-inflammatory phenotypes and functions adopted by microglia and macrophages are fueled by the potential for inflammatory cells to both exacerbate neurodegeneration and promote repair/disease resolution. The stimulation-based, M1/M2 classification system has emerged over the last decade as a common language to discuss macrophage and microglia heterogeneity across different fields. However, discontinuities between phenotypic markers and function create potential hurdles for the utility of the M1/M2 system in the development of effective immunomodulatory therapeutics for neuroinflammation. A framework to approach macrophage and microglia heterogeneity from a function-based phenotypic approach comes from rapidly emerging evidence that metabolic processes regulate immune cell activation. This concept of immunometabolism, however, is only beginning to unfold in the study of neurodegeneration and has yet to receive much focus in the context of neurotrauma. In this review, we first discuss the current views of macrophage and microglia heterogeneity and limitations of the M1/M2 classification system for neuropathological studies. We then review and discuss the current literature supporting metabolism as a regulator of microglia function in vitro. Lastly, we evaluate the evidence that metabolism regulates microglia and macrophage phenotype in vivo in models of Alzheimer's disease (AD), stroke, traumatic brain injury (TBI) and spinal cord injury (SCI).
Collapse
Affiliation(s)
- Nicholas A Devanney
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Andrew N Stewart
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America; Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - John C Gensel
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America; Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America.
| |
Collapse
|
|
40
|
Gao J, Su G, Liu J, Zhang J, Zhou J, Liu X, Tian Y, Zhang Z. Mechanisms of Inhibition of Excessive Microglial Activation by Melatonin. J Mol Neurosci 2020; 70:1229-1236. [PMID: 32222896 DOI: 10.1007/s12031-020-01531-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 03/12/2020] [Indexed: 12/22/2022]
Abstract
As the innate immune cells that permanently reside in the central nervous system (CNS), microglia play an increasingly important role in maintaining brain function. Normally, microglia act as resting phenotype, which can be activated by various types of stimuli and release a variety of inflammatory mediators. Melatonin is an endogenous rhythmic hormone secreted principally by the pineal gland. Increasing evidence suggests that melatonin can detoxify reactive oxygen species (ROS) and prevent microglia from over-activation. This review summarizes the mechanisms of melatonin in inhibiting excessive activation of microglia and demonstrates the feasibility of melatonin in the treatment of diseases related to microglial over-activation.
Collapse
Affiliation(s)
- Juan Gao
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Gang Su
- Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China
| | - Jifei Liu
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Jiajia Zhang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Juanping Zhou
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Xiaoyan Liu
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Ye Tian
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China
| | - Zhenchang Zhang
- Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China.
| |
Collapse
|
|
41
|
Lauro C, Limatola C. Metabolic Reprograming of Microglia in the Regulation of the Innate Inflammatory Response. Front Immunol 2020; 11:493. [PMID: 32265936 PMCID: PMC7099404 DOI: 10.3389/fimmu.2020.00493] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 03/04/2020] [Indexed: 12/11/2022] Open
Abstract
Microglia sustain normal brain functions continuously monitoring cerebral parenchyma to detect neuronal activities and alteration of homeostatic processes. The metabolic pathways involved in microglia activity adapt at and contribute to cell phenotypes. While the mitochondrial oxidative phosphorylation is highly efficient in ATP production, glycolysis enables microglia with a faster rate of ATP production, with the generation of intermediates for cell growth and cytokine production. In macrophages, pro-inflammatory stimuli induce a metabolic switch from oxidative phosphorylation to glycolysis, a phenomenon similar to the Warburg effect well characterized in tumor cells. Modification of metabolic functions allows macrophages to properly respond to a changing environment and many evidence suggest that, similarly to macrophages, microglial cells are capable of a plastic use of energy substrates. Neuroinflammation is a common condition in many neurodegenerative diseases and the metabolic reprograming of microglia has been reported in neurodegeneration. Here we review the existing data on microglia metabolism and the connections with neuroinflammatory diseases, highlighting how metabolic changes contribute to module the homeostatic functions of microglia.
Collapse
Affiliation(s)
- Clotilde Lauro
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Cristina Limatola
- Laboratory Affiliated to Istituto Pasteur Italia- Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.,IRCCS NeuroMed, Pozzilli, Italy
| |
Collapse
|
|
42
|
Kim JD, Yoon NA, Jin S, Diano S. Microglial UCP2 Mediates Inflammation and Obesity Induced by High-Fat Feeding. Cell Metab 2019; 30:952-962.e5. [PMID: 31495690 PMCID: PMC7251564 DOI: 10.1016/j.cmet.2019.08.010] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/01/2019] [Accepted: 08/09/2019] [Indexed: 11/19/2022]
Abstract
Microglia play a crucial role in immune responses, including inflammation. Diet-induced obesity (DIO) triggers microglia activation and hypothalamic inflammation as early as 3 days after high-fat diet (HFD) exposure, before changes in body weight occur. The intracellular mechanism(s) responsible for HFD-induced microglia activation is ill defined. Here, we show that in vivo, HFD induced a rapid and transient increase in uncoupling protein 2 (Ucp2) mRNA expression together with changes in mitochondrial dynamics. Selective microglial deletion of Ucp2 prevented changes in mitochondrial dynamics and function, microglia activation, and hypothalamic inflammation. In association with these, male and female mice were protected from HFD-induced obesity, showing decreased feeding and increased energy expenditure that were associated with changes in the synaptic input organization and activation of the anorexigenic hypothalamic POMC neurons and astrogliosis. Together, our data point to a fuel-availability-driven mitochondrial mechanism as a major player of microglia activation in the central regulation of DIO.
Collapse
Affiliation(s)
- Jung Dae Kim
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Nal Ae Yoon
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Sungho Jin
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Sabrina Diano
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples 80131, Italy.
| |
Collapse
|
|
43
|
Ajmone-Cat MA, Spinello C, Valenti D, Franchi F, Macrì S, Vacca RA, Laviola G. Brain-Immune Alterations and Mitochondrial Dysfunctions in a Mouse Model of Paediatric Autoimmune Disorder Associated with Streptococcus: Exacerbation by Chronic Psychosocial Stress. J Clin Med 2019; 8:1514. [PMID: 31547098 PMCID: PMC6833026 DOI: 10.3390/jcm8101514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 09/17/2019] [Accepted: 09/18/2019] [Indexed: 12/18/2022] Open
Abstract
Adverse psychosocial experiences have been shown to modulate individual responses to immune challenges and affect mitochondrial functions. The aim of this study was to investigate inflammation and immune responses as well as mitochondrial bioenergetics in an experimental model of Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). Starting in adolescence (postnatal day 28), male SJL/J mice were exposed to five injections (interspaced by two weeks) with Group-A beta-haemolytic streptococcus (GAS) homogenate. Mice were exposed to chronic psychosocial stress, in the form of protracted visual exposure to an aggressive conspecific, for four weeks. Our results indicate that psychosocial stress exacerbated individual response to GAS administrations whereby mice exposed to both treatments exhibited altered cytokine and immune-related enzyme expression in the hippocampus and hypothalamus. Additionally, they showed impaired mitochondrial respiratory chain complexes IV and V, and reduced adenosine triphosphate (ATP) production by mitochondria and ATP content. These brain abnormalities, observed in GAS-Stress mice, were associated with blunted titers of plasma corticosterone. Present data support the hypothesis that challenging environmental conditions, in terms of chronic psychosocial stress, may exacerbate the long-term consequences of exposure to GAS processes through the promotion of central immunomodulatory and oxidative stress.
Collapse
Affiliation(s)
- Maria Antonietta Ajmone-Cat
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161 Rome, Italy.
| | - Chiara Spinello
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161 Rome, Italy.
- Department of Mechanical and Aerospace Engineering, New York University Tandon School of Engineering, Brooklyn, NY 11201, USA.
| | - Daniela Valenti
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Council of Research, Via Giovanni Amendola 122/O - 70126 Bari, Italy.
| | - Francesca Franchi
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161 Rome, Italy.
| | - Simone Macrì
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161 Rome, Italy.
| | - Rosa Anna Vacca
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Council of Research, Via Giovanni Amendola 122/O - 70126 Bari, Italy.
| | - Giovanni Laviola
- Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161 Rome, Italy.
| |
Collapse
|
|
44
|
Anderson AJ, Jackson TD, Stroud DA, Stojanovski D. Mitochondria-hubs for regulating cellular biochemistry: emerging concepts and networks. Open Biol 2019; 9:190126. [PMID: 31387448 PMCID: PMC6731593 DOI: 10.1098/rsob.190126] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mitochondria are iconic structures in biochemistry and cell biology, traditionally referred to as the powerhouse of the cell due to a central role in energy production. However, modern-day mitochondria are recognized as key players in eukaryotic cell biology and are known to regulate crucial cellular processes, including calcium signalling, cell metabolism and cell death, to name a few. In this review, we will discuss foundational knowledge in mitochondrial biology and provide snapshots of recent advances that showcase how mitochondrial function regulates other cellular responses.
Collapse
Affiliation(s)
- Alexander J Anderson
- Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Thomas D Jackson
- Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - David A Stroud
- Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Diana Stojanovski
- Department of Biochemistry and Molecular Biology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, 3010, Australia
| |
Collapse
|
|
45
|
UCP2 ameliorates mitochondrial dysfunction, inflammation, and oxidative stress in lipopolysaccharide-induced acute kidney injury. Int Immunopharmacol 2019; 71:336-349. [DOI: 10.1016/j.intimp.2019.03.043] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 03/21/2019] [Indexed: 12/19/2022]
|
|
46
|
Insulin treatment protects the brain against neuroinflammation by reducing cerebral cytokines and modulating mitochondrial function. Brain Res Bull 2019; 149:120-128. [PMID: 31002914 DOI: 10.1016/j.brainresbull.2019.04.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 04/12/2019] [Accepted: 04/14/2019] [Indexed: 12/22/2022]
Abstract
In the central nervous system, glial cells protect the brain against neuronal stress by inducing inflammatory responses; namely, intracellular signaling and cytokine production. However, chronic inflammation is often associated with degenerative diseases that can damage hormone signaling and mitochondrial function. Lipopolysaccharide (LPS) induces neuroinflammation by stimulating the production of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α); moreover, it generates oxidative stress and impairs cognitive functions. The aim of the present study was to assess the therapeutic efficacy of intracerebroventricular (i.c.v.) injections of insulin against neuroinflammation. Inflammation was first induced in male Wistar rats (60 days old, n = 12/group) through an intraperitoneal injection of 0.1 mg/kg LPS. The i.c.v. insulin treatment at a 0.5 mU dose was initiated 4 h later and administered once a day for 5 days. Thereafter, the spatial memory of the rats was assessed, and the hippocampus and cortex were later dissected for biochemical analyses. Our results showed that LPS induced cognitive function impairments, but the insulin treatment reversed these effects. Whereas the levels of brain-derived neurotrophic factor and beta-nerve growth factor in the hippocampus were not altered by LPS, they were decreased in the cortex by insulin. The IL-1β and TNF-α levels were increased in the cortex and hippocampus following exposure to LPS, but insulin reversed these effects. Evaluation of the H2O2levels and mitochondrial membrane potential revealed that LPS modulated mitochondrial function, an effect that was also reversed by insulin. Moreover, LPS induced oxidative stress by decreasing the superoxide dismutase and catalase activities and glutathione and sulfhydryl levels. Furthermore, the levels of oxidative stress probes/markers (i.e.,2',7'-dichlorodihydrofluoresceindiacetateand nitrite) were higher in the LPS-treated rats. These effects were all reversed in the cortex and hippocampus by insulin treatment. Our results suggest a potential role for insulin as a therapeutic drug against inflammatory diseases associated with mitochondrial dysfunction in the brain.
Collapse
|
|
47
|
Hu L, Zhang S, Wen H, Liu T, Cai J, Du D, Zhu D, Chen F, Xia C. Melatonin decreases M1 polarization via attenuating mitochondrial oxidative damage depending on UCP2 pathway in prorenin-treated microglia. PLoS One 2019; 14:e0212138. [PMID: 30742657 PMCID: PMC6370243 DOI: 10.1371/journal.pone.0212138] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 01/28/2019] [Indexed: 12/24/2022] Open
Abstract
Accumulating evidence suggests that neuroinflammation and oxidative stress in cardiovascular center contribute to the pathological processes underlying hypertension. Microglia activation triggers the inflammation and oxidative stress. Melatonin is a documented potent anti-inflammatory regent and antioxidant, the underlying roles of melatonin in regulating microglia activation via mitochondria remain unclear. In present study, we investigated the protective role of melatonin in decreasing M1 phenotype switching via attenuating mitochondrial oxidative damage in dependence on uncoupling protein 2 (UCP2) pathway in microglia. Prorenin (20 nmol/L; 24 hr) was used to induce inflammation in cultured microglia. Mitochondrial morphology was detected by transmission electron microscope. The reactive oxygen species (ROS) production by using DCFH-DA fluorescence imaging and mitochondrial membrane potential (MMP, ΔΨm) was evaluated by JC-1 staining. The indicator of the redox status as the ratio of the amount of total NADP+ to total NADPH, and the expression of 6 subunits of NADPH oxidase is measured. The pro-inflammatory cytokines releasing was measured by qPCR. UCP2 and activated AMPKα (p-AMPKα) expression were examined by immunoblot. Melatonin (100 μM) markedly alleviated the M1 microglia phenotype shifting and abnormal mitochondria morphology. Melatonin attenuated prorenin-induced ΔΨm increasing and ROS overproduction. Melatonin decreased the redox ratio (NADP+/NADPH) and the p47phox and gp91phox subunits of NADPH oxidase expression in prorenin-treated microglia. These effects were reversed in the presence of UCP2 siRNA. Our results suggested that the protective effect of melatonin against prorenin-induced M1 phenotype switching via attenuating mitochondrial oxidative damage depending on UCP2 upregulation in prorenin-treated microglia.
Collapse
Affiliation(s)
- Li Hu
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, P.R. China
| | - Shutian Zhang
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, P.R. China
| | - Haoyu Wen
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, P.R. China
| | - Tianfeng Liu
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, P.R. China
| | - Jian Cai
- Department of neurology, Renji Hospital, Shanghai Jiaotong University, Shanghai, P.R. China
| | - Dongshu Du
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, P.R. China
| | - Danian Zhu
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, P.R. China
| | - Fuxue Chen
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, P.R. China
- * E-mail: (FXC); (CMX)
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, Basic Medicine College, Fudan University, Shanghai, P.R. China
- * E-mail: (FXC); (CMX)
| |
Collapse
|
|
48
|
Nair S, Sobotka KS, Joshi P, Gressens P, Fleiss B, Thornton C, Mallard C, Hagberg H. Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo. Glia 2019; 67:1047-1061. [PMID: 30637805 DOI: 10.1002/glia.23587] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/21/2018] [Accepted: 12/21/2018] [Indexed: 12/18/2022]
Abstract
Accumulating evidence suggests that changes in the metabolic signature of microglia underlie their response to inflammation. We sought to increase our knowledge of how pro-inflammatory stimuli induce metabolic changes. Primary microglia exposed to lipopolysaccharide (LPS)-expressed excessive fission leading to more fragmented mitochondria than tubular mitochondria. LPS-mediated Toll-like receptor 4 (TLR4) activation also resulted in metabolic reprogramming from oxidative phosphorylation to glycolysis. Blockade of mitochondrial fission by Mdivi-1, a putative mitochondrial division inhibitor led to the reversal of the metabolic shift. Mdivi-1 treatment also normalized the changes caused by LPS exposure, namely an increase in mitochondrial reactive oxygen species production and mitochondrial membrane potential as well as accumulation of key metabolic intermediate of TCA cycle succinate. Moreover, Mdivi-1 treatment substantially reduced LPS induced cytokine and chemokine production. Finally, we showed that Mdivi-1 treatment attenuated expression of genes related to cytotoxic, repair, and immunomodulatory microglia phenotypes in an in vivo neuroinflammation paradigm. Collectively, our data show that the activation of microglia to a classically pro-inflammatory state is associated with a switch to glycolysis that is mediated by mitochondrial fission, a process which may be a pharmacological target for immunomodulation.
Collapse
Affiliation(s)
- Syam Nair
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kristina S Sobotka
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Pooja Joshi
- PROTECT, INSERM, Université Paris Diderot, Paris, France
| | - Pierre Gressens
- PROTECT, INSERM, Université Paris Diderot, Paris, France
- Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom
| | - Bobbi Fleiss
- PROTECT, INSERM, Université Paris Diderot, Paris, France
- Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Claire Thornton
- Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom
| | - Carina Mallard
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Henrik Hagberg
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom
- Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
|
49
|
Ježek P, Holendová B, Garlid KD, Jabůrek M. Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling. Antioxid Redox Signal 2018; 29:667-714. [PMID: 29351723 PMCID: PMC6071544 DOI: 10.1089/ars.2017.7225] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1-5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. CRITICAL ISSUES A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling. FUTURE DIRECTIONS Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667-714.
Collapse
Affiliation(s)
- Petr Ježek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Blanka Holendová
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Keith D Garlid
- 2 UCLA Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA , Los Angeles, California
| | - Martin Jabůrek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| |
Collapse
|
|
50
|
Angajala A, Lim S, Phillips JB, Kim JH, Yates C, You Z, Tan M. Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism. Front Immunol 2018; 9:1605. [PMID: 30050539 PMCID: PMC6052888 DOI: 10.3389/fimmu.2018.01605] [Citation(s) in RCA: 296] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/27/2018] [Indexed: 12/20/2022] Open
Abstract
Lack of immune system cells or impairment in differentiation of immune cells is the basis for many chronic diseases. Metabolic changes could be the root cause for this immune cell impairment. These changes could be a result of altered transcription, cytokine production from surrounding cells, and changes in metabolic pathways. Immunity and mitochondria are interlinked with each other. An important feature of mitochondria is it can regulate activation, differentiation, and survival of immune cells. In addition, it can also release signals such as mitochondrial DNA (mtDNA) and mitochondrial ROS (mtROS) to regulate transcription of immune cells. From current literature, we found that mitochondria can regulate immunity in different ways. First, alterations in metabolic pathways (TCA cycle, oxidative phosphorylation, and FAO) and mitochondria induced transcriptional changes can lead to entirely different outcomes in immune cells. For example, M1 macrophages exhibit a broken TCA cycle and have a pro-inflammatory role. By contrast, M2 macrophages undergo β-oxidation to produce anti-inflammatory responses. In addition, amino acid metabolism, especially arginine, glutamine, serine, glycine, and tryptophan, is critical for T cell differentiation and macrophage polarization. Second, mitochondria can activate the inflammatory response. For instance, mitochondrial antiviral signaling and NLRP3 can be activated by mitochondria. Third, mitochondrial mass and mobility can be influenced by fission and fusion. Fission and fusion can influence immune functions. Finally, mitochondria are placed near the endoplasmic reticulum (ER) in immune cells. Therefore, mitochondria and ER junction signaling can also influence immune cell metabolism. Mitochondrial machinery such as metabolic pathways, amino acid metabolism, antioxidant systems, mitochondrial dynamics, mtDNA, mitophagy, and mtROS are crucial for immune functions. Here, we have demonstrated how mitochondria coordinate to alter immune responses and how changes in mitochondrial machinery contribute to alterations in immune responses. A better understanding of the molecular components of mitochondria is necessary. This can help in the development of safe and effective immune therapy or prevention of chronic diseases. In this review, we have presented an updated prospective of the mitochondrial machinery that drives various immune responses.
Collapse
Affiliation(s)
- Anusha Angajala
- Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States.,Department of Biology, Center for Cancer Research, Tuskegee University, Tuskegee, AL, United States
| | - Sangbin Lim
- Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
| | - Joshua B Phillips
- Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
| | - Jin-Hwan Kim
- Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
| | - Clayton Yates
- Department of Biology, Center for Cancer Research, Tuskegee University, Tuskegee, AL, United States
| | - Zongbing You
- Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Ming Tan
- Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, United States
| |
Collapse
|