|
1
|
Sun M, Liu Y, Wang X, Wang L. HPGD: An Intermediate Player in Microglial Polarization and Multiple Sclerosis Regulated by Nr4a1. Mol Neurobiol 2025; 62:271-287. [PMID: 38842672 DOI: 10.1007/s12035-024-04280-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 06/02/2024] [Indexed: 06/07/2024]
Abstract
HPGD encodes 15-Hydroxyprostaglandin dehydrogenase catalyzing the decomposition of prostaglandin E2 and has not been reported in multiple sclerosis (MS). We previously found that Nr4a1 regulated microglia polarization and inhibited the progression of experimental autoimmune encephalomyelitis (EAE). Bioinformatics analysis suggested that HPGD might be regulated by Nr4a1. Therefore, this study aimed to explore the role of HPGD in microglia polarization and determine whether HPGD mediates the inhibition of EAE by Nr4a1. C57BL/6 mice were treated with MOG35-55 peptide to induce EAE. BV-2 cells were treated with LPS/IL-4 to induce M1/M2 polarization. We then analyzed the pathological changes of spinal cord tissue, detected the expression levels of M1/M2 genes in tissues and cells, and explored the effect of HPGD on PPARγ activation to clarify the role of HPGD in EAE. The interaction between HPGD and Nr4a1 was verified by ChIP and pull-down assay. HPGD was downregulated in the spinal cord of EAE mice and HPGD overexpression alleviated the progression of EAE. Experiments in vitro and in vivo revealed that HPGD inhibited M1 polarization, promoted M2 polarization and increased PPARγ-DNA complex level. Nr4a1 could bind to the promoter of HPGD and its overexpression increased HPGD level. HPGD overexpression (or knockdown) reversed the effect of Nr4a1 knockdown (or overexpression) on M1/2 polarization. HPGD is regulated by Nr4a1 and inhibits the progression of EAE through shifting the M1/M2 polarization and promoting the activation of PPARγ signaling pathway. This study provides potential targets and basis for the development of MS therapeutic drugs.
Collapse
Affiliation(s)
- Mengyang Sun
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yang Liu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaowan Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Limei Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| |
Collapse
|
|
2
|
Dhir S, Derue H, Ribeiro-da-Silva A. Temporal changes of spinal microglia in murine models of neuropathic pain: a scoping review. Front Immunol 2024; 15:1460072. [PMID: 39735541 PMCID: PMC11671780 DOI: 10.3389/fimmu.2024.1460072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 11/18/2024] [Indexed: 12/31/2024] Open
Abstract
Neuropathic pain (NP) is an ineffectively treated, debilitating chronic pain disorder that is associated with maladaptive changes in the central nervous system, particularly in the spinal cord. Murine models of NP looking at the mechanisms underlying these changes suggest an important role of microglia, the resident immune cells of the central nervous system, in various stages of disease progression. However, given the number of different NP models and the resource limitations that come with tracking longitudinal changes in NP animals, many studies fail to truly recapitulate the patterns that exist between pain conditions and temporal microglial changes. This review integrates how NP studies are being carried out in murine models and how microglia changes over time can affect pain behavior in order to inform better study design and highlight knowledge gaps in the field. 258 peer-reviewed, primary source articles looking at spinal microglia in murine models of NP were selected using Covidence. Trends in the type of mice, statistical tests, pain models, interventions, microglial markers and temporal pain behavior and microglia changes were recorded and analyzed. Studies were primarily conducted in inbred, young adult, male mice having peripheral nerve injury which highlights the lack of generalizability in the data currently being collected. Changes in microglia and pain behavior, which were both increased, were tested most commonly up to 2 weeks after pain initiation despite aberrant microglia activity also being recorded at later time points in NP conditions. Studies using treatments that decrease microglia show decreased pain behavior primarily at the 1- and 2-week time point with many studies not recording pain behavior despite the involvement of spinal microglia dysfunction in their development. These results show the need for not only studying spinal microglia dynamics in a variety of NP conditions at longer time points but also for better clinically relevant study design considerations.
Collapse
Affiliation(s)
- Simran Dhir
- Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada
| | - Hannah Derue
- Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Alfredo Ribeiro-da-Silva
- Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada
| |
Collapse
|
|
3
|
Lu W, Wang Y, Wen J. The Roles of RhoA/ROCK/NF-κB Pathway in Microglia Polarization Following Ischemic Stroke. J Neuroimmune Pharmacol 2024; 19:19. [PMID: 38753217 DOI: 10.1007/s11481-024-10118-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 04/21/2024] [Indexed: 05/21/2024]
Abstract
Ischemic stroke is the leading cause of death and disability worldwide. Nevertheless, there still lacks the effective therapies for ischemic stroke. Microglia are resident macrophages of the central nervous system (CNS) and can initiate immune responses and monitor the microenvironment. Microglia are activated and polarize into proinflammatory or anti‑inflammatory phenotype in response to various brain injuries, including ischemic stroke. Proinflammatory microglia could generate immunomodulatory mediators, containing cytokines and chemokines, these mediators are closely associated with secondary brain damage following ischemic stroke. On the contrary, anti-inflammatory microglia facilitate recovery following stroke. Regulating the activation and the function of microglia is crucial in exploring the novel treatments for ischemic stroke patients. Accumulating studies have revealed that RhoA/ROCK pathway and NF-κB are famous modulators in the process of microglia activation and polarization. Inhibiting these key modulators can promote the polarization of microglia to anti-inflammatory phenotype. In this review, we aimed to provide a comprehensive overview on the role of RhoA/ROCK pathway and NF-κB in the microglia activation and polarization, reveal the relationship between RhoA/ROCK pathway and NF-κB in the pathological process of ischemic stroke. In addition, we likewise discussed the drug modulators targeting microglia polarization.
Collapse
Affiliation(s)
- Weizhuo Lu
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Medical Branch, Hefei Technology College, Hefei, China
| | - Yilin Wang
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Jiyue Wen
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
| |
Collapse
|
|
4
|
Wang S, Jiang C, Cao K, Li R, Gao Z, Wang Y. HK2 in microglia and macrophages contribute to the development of neuropathic pain. Glia 2024; 72:396-410. [PMID: 37909251 DOI: 10.1002/glia.24482] [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: 06/22/2023] [Revised: 09/29/2023] [Accepted: 10/04/2023] [Indexed: 11/02/2023]
Abstract
Neuropathic pain is a complex pain condition accompanied by prominent neuroinflammation involving activation of both central and peripheral immune cells. Metabolic switch to glycolysis is an important feature of activated immune cells. Hexokinase 2 (HK2), a key glycolytic enzyme enriched in microglia, has recently been shown important in regulating microglial functions. Whether and how HK2 is involved in neuropathic pain-related neuroinflammation remains unknown. Using a HK2-tdTomato reporter line, we found that HK2 was prominently elevated in spinal microglia. Pharmacological inhibition of HK2 effectively alleviated nerve injury-induced acute mechanical pain. However, selective ablation of Hk2 in microglia reduced microgliosis in the spinal dorsal horn (SDH) with little analgesic effects. Further analyses showed that nerve injury also significantly induced HK2 expression in dorsal root ganglion (DRG) macrophages. Deletion of Hk2 in myeloid cells, including both DRG macrophages and spinal microglia, led to the alleviation of mechanical pain during the first week after injury, along with attenuated microgliosis in the ipsilateral SDH, macrophage proliferation in DRGs, and suppressed inflammatory responses in DRGs. These data suggest that HK2 plays an important role in regulating neuropathic pain-related immune cell responses at acute phase and that HK2 contributes to neuropathic pain onset primarily through peripheral monocytes and DRG macrophages rather than spinal microglia.
Collapse
Affiliation(s)
- Siyuan Wang
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chao Jiang
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kelei Cao
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
- The MOE Frontier Research Center of Brain & Brain-machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
| | - Run Li
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhihua Gao
- Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
- The MOE Frontier Research Center of Brain & Brain-machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
| | - Yue Wang
- Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
5
|
Chen H, Guo Z, Sun Y, Dai X. The immunometabolic reprogramming of microglia in Alzheimer's disease. Neurochem Int 2023; 171:105614. [PMID: 37748710 DOI: 10.1016/j.neuint.2023.105614] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/08/2023] [Accepted: 09/14/2023] [Indexed: 09/27/2023]
Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative disorder (NDD). In the central nervous system (CNS), immune cells like microglia could reprogram intracellular metabolism to alter or exert cellular immune functions in response to environmental stimuli. In AD, microglia could be activated and differentiated into pro-inflammatory or anti-inflammatory phenotypes, and these differences in cellular phenotypes resulted in variance in cellular energy metabolism. Considering the enormous energy requirement of microglia for immune functions, the changes in mitochondria-centered energy metabolism and substrates of microglia are crucial for the cellular regulation of immune responses. Here we reviewed the mechanisms of microglial metabolic reprogramming by analyzing their flexible metabolic patterns and changes that occurred in their metabolism during the development of AD. Further, we summarized the role of drugs in modulating immunometabolic reprogramming to prevent neuroinflammation, which may shed light on a new research direction for AD treatment.
Collapse
Affiliation(s)
- Hongli Chen
- Beijing Key Laboratory of Bioactive Substances and Functional Food, College of Biochemical Engineering, Beijing Union University, Beijing, 100023, China
| | - Zichen Guo
- Beijing Key Laboratory of Bioactive Substances and Functional Food, College of Biochemical Engineering, Beijing Union University, Beijing, 100023, China
| | - Yaxuan Sun
- Beijing Key Laboratory of Bioactive Substances and Functional Food, College of Biochemical Engineering, Beijing Union University, Beijing, 100023, China
| | - Xueling Dai
- Beijing Key Laboratory of Bioactive Substances and Functional Food, College of Biochemical Engineering, Beijing Union University, Beijing, 100023, China.
| |
Collapse
|
|
6
|
Babalola JA, Lang M, George M, Stracke A, Tam-Amersdorfer C, Itxaso I, Lucija D, Tadic J, Schilcher I, Loeffler T, Flunkert S, Prokesch M, Leitinger G, Lass A, Hutter-Paier B, Panzenboeck U, Hoefler G. Astaxanthin enhances autophagy, amyloid beta clearance and exerts anti-inflammatory effects in in vitro models of Alzheimer's disease-related blood brain barrier dysfunction and inflammation. Brain Res 2023; 1819:148518. [PMID: 37579986 DOI: 10.1016/j.brainres.2023.148518] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/22/2023] [Accepted: 08/02/2023] [Indexed: 08/16/2023]
Abstract
Defective degradation and clearance of amyloid-β as well as inflammation per se are crucial players in the pathology of Alzheimer's disease (AD). A defective transport across the blood-brain barrier is causative for amyloid-β (Aβ) accumulation in the brain, provoking amyloid plaque formation. Using primary porcine brain capillary endothelial cells and murine organotypic hippocampal slice cultures as in vitro models of AD, we investigated the effects of the antioxidant astaxanthin (ASX) on Aβ clearance and neuroinflammation. We report that ASX enhanced the clearance of misfolded proteins in primary porcine brain capillary endothelial cells by inducing autophagy and altered the Aβ processing pathway. We observed a reduction in the expression levels of intracellular and secreted amyloid precursor protein/Aβ accompanied by an increase in ABC transporters ABCA1, ABCG1 as well as low density lipoprotein receptor-related protein 1 mRNA levels. Furthermore, ASX treatment increased autophagic flux as evidenced by increased lipidation of LC3B-II as well as reduced protein expression of phosphorylated S6 ribosomal protein and mTOR. In LPS-stimulated brain slices, ASX exerted anti-inflammatory effects by reducing the secretion of inflammatory cytokines while shifting microglia polarization from M1 to M2 phenotype. Our data suggest ASX as potential therapeutic compound ameliorating AD-related blood brain barrier impairment and inflammation.
Collapse
Affiliation(s)
| | - Magdalena Lang
- Otto Loewi Research Center, Division of Immunology, Medical University of Graz, Austria
| | - Meekha George
- Department of Obstetrics and Gynaecology, Medical University of Graz, Austria
| | - Anika Stracke
- Otto Loewi Research Center, Division of Immunology, Medical University of Graz, Austria
| | | | | | | | - Jelena Tadic
- Institute of Molecular Biosciences, University of Graz, Austria
| | | | | | | | | | - Gerd Leitinger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Achim Lass
- Institute of Molecular Biosciences, University of Graz, Austria
| | | | - Ute Panzenboeck
- Otto Loewi Research Center, Division of Immunology, Medical University of Graz, Austria
| | - Gerald Hoefler
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Austria.
| |
Collapse
|
|
7
|
Lu W, Chen Z, Wen J. The role of RhoA/ROCK pathway in the ischemic stroke-induced neuroinflammation. Biomed Pharmacother 2023; 165:115141. [PMID: 37437375 DOI: 10.1016/j.biopha.2023.115141] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/03/2023] [Accepted: 07/07/2023] [Indexed: 07/14/2023] Open
Abstract
It is widely known that ischemic stroke is the prominent cause of death and disability. To date, neuroinflammation following ischemic stroke represents a complex event, which is an essential process and affects the prognosis of both experimental stroke animals and stroke patients. Intense neuroinflammation occurring during the acute phase of stroke contributes to neuronal injury, BBB breakdown, and worse neurological outcomes. Inhibition of neuroinflammation may be a promising target in the development of new therapeutic strategies. RhoA is a small GTPase protein that activates a downstream effector, ROCK. The up-regulation of RhoA/ROCK pathway possesses important roles in promoting the neuroinflammation and mediating brain injury. In addition, nuclear factor-kappa B (NF-κB) is another vital regulator of ischemic stroke-induced neuroinflammation through regulating the functions of microglial cells and astrocytes. After stroke onset, the microglial cells and astrocytes are activated and undergo the morphological and functional changes, thereby deeply participate in a complicated neuroinflammation cascade. In this review, we focused on the relationship among RhoA/ROCK pathway, NF-κB and glial cells in the neuroinflammation following ischemic stroke to reveal new strategies for preventing the intense neuroinflammation.
Collapse
Affiliation(s)
- Weizhuo Lu
- Medical Branch, Hefei Technology College, Hefei, China
| | - Zhiwu Chen
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
| | - Jiyue Wen
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
| |
Collapse
|
|
8
|
Chen N, Wang YL, Sun HF, Wang ZY, Zhang Q, Fan FY, Ma YC, Liu FX, Zhang YK. Potential regulatory effects of stem cell exosomes on inflammatory response in ischemic stroke treatment. World J Stem Cells 2023; 15:561-575. [PMID: 37424949 PMCID: PMC10324506 DOI: 10.4252/wjsc.v15.i6.561] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 04/22/2023] [Accepted: 05/16/2023] [Indexed: 06/26/2023] Open
Abstract
The high incidence and disability rates of stroke pose a heavy burden on society. Inflammation is a significant pathological reaction that occurs after an ischemic stroke. Currently, therapeutic methods, except for intravenous thrombolysis and vascular thrombectomy, have limited time windows. Mesenchymal stem cells (MSCs) can migrate, differentiate, and inhibit inflammatory immune responses. Exosomes (Exos), which are secretory vesicles, have the characteristics of the cells from which they are derived, making them attractive targets for research in recent years. MSC-derived exosomes can attenuate the inflammatory response caused by cerebral stroke by modulating damage-associated molecular patterns. In this review, research on the inflammatory response mechanisms associated with Exos therapy after an ischemic injury is discussed to provide a new approach to clinical treatment.
Collapse
Affiliation(s)
- Na Chen
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yan-Lin Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Hui-Fang Sun
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhuo-Ya Wang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qi Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Fei-Yan Fan
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Yu-Cheng Ma
- First School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Fei-Xiang Liu
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Yun-Ke Zhang
- Department of Neurology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- School of Rehabilitation Medicine, Henan University of Chinese Medicine, Zhengzhou 450008, Henan Province, China
| |
Collapse
|
|
9
|
Syamprasad NP, Rajdev B, Jain S, Panda SR, Puppala ER, Chaudhari P, Vaidya JR, Kumar GJ, Naidu VGM. Pivotal role of AKR1B1 in pathogenesis of colitis associated colorectal carcinogenesis. Int Immunopharmacol 2023; 119:110145. [PMID: 37044030 DOI: 10.1016/j.intimp.2023.110145] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/27/2023] [Accepted: 03/31/2023] [Indexed: 04/14/2023]
Abstract
Identifying the target linking inflammation and oxidative stress to aggravate the disease progression will help to prevent colitis associated carcinogenesis. Since AKR1B1 overexpression is observed in inflammatory diseases and various cancers, we have investigated the role of AKR1B1 in colitis-associated colon carcinogenesis with the aid of epalrestat and its potent analogue NARI-29 (investigational molecule) as pharmacological probes. A TNF-α inducible NF-κB reporter cell line (GloResponse™ NF-κB-RE-luc2P HEK293) and dextran sodium sulfate (DSS) and 1,2 dimethyl hydrazine (DMH))-induced mouse model was used to investigate our hypothesis in vitro and in vivo. Clinically, an increased expression of AKR1B1 was observed in patients with ulcerative colitis. Our in vitro and in vivo findings suggest that the AKR1B1 modulated inflammation and ROS generation for the progression of colitis to colon cancer. AKR1B1 overexpression was observed in DSS + DMH-treated mice colons. Moreover, we could observe histopathological changes like immune cell infiltration, aberrant crypt foci, and tumour formation in DC groups. Mechanistically, we have witnessed modulation of the IKK/IκB/NF-κB and Akt/FOXO-3a/DR axis, increased inflammatory cytokines, increased expression of proliferative markers, Ki-67 and PCNA, and accumulation of β-catenin in the colon epithelium. However, pharmacological inhibition of AKR1B1 using NARI-29 or EPS has reversed the clinical, histopathological, and molecular alterations induced by DSS + DMH, confirming the obvious role of AKR1B1 in the promotion of colitis-associated carcinogenesis. In conclusion, our findings suggest that AKR1B1 targeted therapy could be a promising strategy for preventing CA-CRC and NARI-29 could be developed as a potent AKR1B1 inhibitor.
Collapse
Affiliation(s)
- N P Syamprasad
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam 781101, India
| | - Bishal Rajdev
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam 781101, India
| | - Siddhi Jain
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam 781101, India
| | - Samir Ranjan Panda
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam 781101, India
| | - Eswara Rao Puppala
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam 781101, India
| | - Pradip Chaudhari
- Advance Centre for Treatment Research & Education in Cancer, Tata Memorial Centre, (ACTREC), Plot No. 1 & 2, Sector 22, Kharghar, Navi Mumbai, Maharashtra 410210, India
| | - Jayathirtha Rao Vaidya
- Fluoro Agro Chemicals Department and AcSIR-Ghaziabad, CSIR-Indian Institute of Chemical Technology, Uppal Road Tarnaka, Hyderabad, Telangana 500007, India
| | - Gangasani Jagadeesh Kumar
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam 781101, India.
| | - V G M Naidu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research Guwahati, Sila village, Changsari, Assam 781101, India.
| |
Collapse
|
|
10
|
Zhang T, Wu J, Yao X, Zhang Y, Wang Y, Han Y, Wu Y, Xu Z, Lan J, Han S, Zou H, Sun Q, Wang D, Zhang J, Wang G. The Aldose Reductase Inhibitor Epalrestat Maintains Blood-Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia. Mol Neurobiol 2023; 60:3741-3757. [PMID: 36940077 DOI: 10.1007/s12035-023-03304-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 03/08/2023] [Indexed: 03/21/2023]
Abstract
Excessive activation of aldose reductase (AR) in the brain is a risk factor for aggravating cerebral ischemia injury. Epalrestat is the only AR inhibitor with proven safety and efficacy, which is used in the clinical treatment of diabetic neuropathy. However, the molecular mechanisms underlying the neuroprotection of epalrestat remain unknown in the ischemic brain. Recent studies have found that blood-brain barrier (BBB) damage was mainly caused by increased apoptosis and autophagy of brain microvascular endothelial cells (BMVECs) and decreased expression of tight junction proteins. Thus, we hypothesized that the protective effect of epalrestat is mainly related to regulating the survival of BMVECs and tight junction protein levels after cerebral ischemia. To test this hypothesis, a mouse model of cerebral ischemia was established by permanent middle cerebral artery ligation (pMCAL), and the mice were treated with epalrestat or saline as a control. Epalrestat reduced the ischemic volume, enhanced BBB function, and improved the neurobehavior after cerebral ischemia. In vitro studies revealed that epalrestat increased the expression of tight junction proteins, and reduced the levels of cleaved-caspase3 and LC3 proteins in mouse BMVECs (bEnd.3 cells) exposed to oxygen-glucose deprivation (OGD). In addition, bicalutamide (an AKT inhibitor) and rapamycin (an mTOR inhibitor) increased the epalrestat-induced reduction in apoptosis and autophagy related protein levels in bEnd.3 cells with OGD treatment. Our findings suggest that epalrestat improves BBB function, which may be accomplished by reducing AR activation, promoting tight junction proteins expression, and upregulating AKT/mTOR signaling pathway to inhibit apoptosis and autophagy in BMVECs.
Collapse
Affiliation(s)
- Tongshuai Zhang
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Jinrong Wu
- Department of Anaesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Xinmin Yao
- Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang, China
| | - Yao Zhang
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Yue Wang
- Department of Anesthesiology, Second Affiliated Hospital of Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Yang Han
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Yun Wu
- The Medical Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Zhenyu Xu
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Jing Lan
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Siyu Han
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Haifeng Zou
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Qixu Sun
- Department of Gastroenterology, Penglai People's Hospital, Yantai, 264117, Shandong, China
| | - Dandan Wang
- Wu Lian De Memorial Hospital, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
| | - Jingyu Zhang
- The Medical Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
| | - Guangyou Wang
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
| |
Collapse
|
|
11
|
Gao S, Jiang Y, Chen Z, Zhao X, Gu J, Wu H, Liao Y, Sun H, Wang J, Chen W. Metabolic Reprogramming of Microglia in Sepsis-Associated Encephalopathy: Insights from Neuroinflammation. Curr Neuropharmacol 2023; 21:1992-2005. [PMID: 36529923 PMCID: PMC10514522 DOI: 10.2174/1570159x21666221216162606] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/29/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022] Open
Abstract
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis that manifests as a range of brain dysfunctions from delirium to coma. It is a relatively common complication of sepsis associated with poor patient prognosis and mortality. The pathogenesis of SAE involves neuroinflammatory responses, neurotransmitter dysfunction, blood-brain barrier (BBB) disruption, abnormal blood flow regulation, etc. Neuroinflammation caused by hyperactivation of microglia is considered to be a key factor in disease development, which can cause a series of chain reactions, including BBB disruption and oxidative stress. Metabolic reprogramming has been found to play a central role in microglial activation and executive functions. In this review, we describe the pivotal role of energy metabolism in microglial activation and functional execution and demonstrate that the regulation of microglial metabolic reprogramming might be crucial in the development of clinical therapeutics for neuroinflammatory diseases like SAE.
Collapse
Affiliation(s)
- Shenjia Gao
- Department of Anesthesiology, Cancer Center, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Yi Jiang
- Department of Anesthesiology, Cancer Center, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Zhaoyuan Chen
- Department of Anesthesiology, Cancer Center, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Xiaoqiang Zhao
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China
| | - Jiahui Gu
- Department of Anesthesiology, Cancer Center, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Han Wu
- Department of Anesthesiology, Cancer Center, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Yun Liao
- Shanghai Medical College of Fudan University, Shanghai, China
| | - Hao Sun
- Department of Anesthesiology, Cancer Center, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Jun Wang
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
| | - Wankun Chen
- Department of Anesthesiology, Cancer Center, Zhongshan Hospital, Fudan University, 180# Feng-Lin Road, Shanghai, 200032, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
- Fudan Zhangjiang Institute, Shanghai, 201203, China
| |
Collapse
|
|
12
|
Zhou J, Xiang W, Zhang K, Zhao Q, Xu Z, Li Z. IL1RAP Knockdown in LPS-Stimulated Normal Human Astrocytes Suppresses LPS-Induced Reactive Astrogliosis and Promotes Neuronal Cell Proliferation. Neurochem Res 2022; 48:1468-1479. [PMID: 36502418 DOI: 10.1007/s11064-022-03811-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 10/09/2022] [Accepted: 10/26/2022] [Indexed: 12/14/2022]
Abstract
The reactivation of astrocytes plays a critical role in spinal cord injury (SCI) repairment. In this study, IL1RAP expression has been found to be upregulated in SCI mice spinal cord, SCI astrocytes, and LPS-stimulated NHAs. Genes correlated with IL1RAP were significantly enriched in cell proliferation relative pathways. In LPS-stimulated NHAs, IL1RAP overexpression promoted NHA cell proliferation, decreased PTEN protein levels, and increased the phosphorylation of Akt and mTOR. IL1RAP overexpression promoted LPS-induced NHA activation and NF-κB signaling activation. Conditioned medium from IL1RAP-overexpressing NHAs inhibited SH-SY5Y cells viability but promoted cell apoptosis. Conclusively, IL1RAP knockdown in LPS-stimulated NHAs could partially suppress LPS-induced reactive astrogliosis, therefore promoting neuronal cell proliferation.
Collapse
Affiliation(s)
- Jiahui Zhou
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Weineng Xiang
- Department of Orthopedics, The First Hospital of Changsha City, Changsha, 410005, China
| | - Kexiang Zhang
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Qun Zhao
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Zhewei Xu
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
| | - Zhiyue Li
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
| |
Collapse
|
|
13
|
The Role of Aldose Reductase in Beta-Amyloid-Induced Microglia Activation. Int J Mol Sci 2022; 23:ijms232315088. [PMID: 36499422 PMCID: PMC9739496 DOI: 10.3390/ijms232315088] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022] Open
Abstract
The occurrence of Alzheimer's disease has been associated with the accumulation of beta-amyloid (β-amyloid) plaques. These plaques activate microglia to secrete inflammatory molecules, which damage neurons in the brain. Thus, understanding the underlying mechanism of microglia activation can provide a therapeutic strategy for alleviating microglia-induced neuroinflammation. The aldose reductase (AR) enzyme catalyzes the reduction of glucose to sorbitol in the polyol pathway. In addition to mediating diabetic complications in hyperglycemic environments, AR also helps regulate inflammation in microglia. However, little is known about the role of AR in β-amyloid-induced inflammation in microglia and subsequent neuronal death. In this study, we confirmed that AR inhibition attenuates increased β-amyloid-induced reactive oxygen species and tumor necrosis factor α secretion by suppressing ERK signaling in BV2 cells. In addition, we are the first to report that AR inhibition reduced the phagocytotic capability and cell migration of BV2 cells in response to β-amyloid. To further investigate the protective role of the AR inhibitor sorbinil in neurons, we co-cultured β-amyloid-induced microglia with stem cell-induced neurons. sorbinil ameliorated neuronal damage in both cells in the co-culture system. In summary, our findings reveal AR regulation of microglia activation as a novel therapeutic target for Alzheimer's disease.
Collapse
|
|
14
|
Chopra N, Menounos S, Choi JP, Hansbro PM, Diwan AD, Das A. Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies. NEUROSCI 2022; 3:1-27. [PMID: 39484675 PMCID: PMC11523733 DOI: 10.3390/neurosci3010001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 12/14/2021] [Indexed: 11/03/2024] Open
Abstract
The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause-effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it.
Collapse
Affiliation(s)
- Neha Chopra
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Kogarah, NSW 2217, Australia; (N.C.); (S.M.); (A.D.D.)
- Spine Service, St. George Hospital, Kogarah, NSW 2217, Australia
| | - Spiro Menounos
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Kogarah, NSW 2217, Australia; (N.C.); (S.M.); (A.D.D.)
| | - Jaesung P Choi
- Centre for Inflammation, Faculty of Science, Centenary Institute, School of Life Sciences, University of Technology Sydney, Sydney, NSW 2050, Australia; (J.P.C.); (P.M.H.)
| | - Philip M Hansbro
- Centre for Inflammation, Faculty of Science, Centenary Institute, School of Life Sciences, University of Technology Sydney, Sydney, NSW 2050, Australia; (J.P.C.); (P.M.H.)
| | - Ashish D Diwan
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Kogarah, NSW 2217, Australia; (N.C.); (S.M.); (A.D.D.)
- Spine Service, St. George Hospital, Kogarah, NSW 2217, Australia
| | - Abhirup Das
- Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Kogarah, NSW 2217, Australia; (N.C.); (S.M.); (A.D.D.)
- Spine Service, St. George Hospital, Kogarah, NSW 2217, Australia
| |
Collapse
|
|
15
|
Guo S, Wang H, Yin Y. Microglia Polarization From M1 to M2 in Neurodegenerative Diseases. Front Aging Neurosci 2022; 14:815347. [PMID: 35250543 PMCID: PMC8888930 DOI: 10.3389/fnagi.2022.815347] [Citation(s) in RCA: 403] [Impact Index Per Article: 134.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Microglia-mediated neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Microglia can be categorized into two opposite types: classical (M1) or alternative (M2), though there’s a continuum of different intermediate phenotypes between M1 and M2, and microglia can transit from one phenotype to another. M1 microglia release inflammatory mediators and induce inflammation and neurotoxicity, while M2 microglia release anti-inflammatory mediators and induce anti-inflammatory and neuroprotectivity. Microglia-mediated neuroinflammation is considered as a double-edged sword, performing both harmful and helpful effects in neurodegenerative diseases. Previous studies showed that balancing microglia M1/M2 polarization had a promising therapeutic prospect in neurodegenerative diseases. We suggest that shifting microglia from M1 to M2 may be significant and we focus on the modulation of microglia polarization from M1 to M2, especially by important signal pathways, in neurodegenerative diseases.
Collapse
|
|
16
|
MALAT1 improves functional recovery after traumatic brain injury through promoting angiogenesis in experimental mice. Brain Res 2022; 1775:147731. [PMID: 34808123 DOI: 10.1016/j.brainres.2021.147731] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 09/09/2021] [Accepted: 11/17/2021] [Indexed: 11/22/2022]
Abstract
As a highly evolutionary conserved lncRNA, MALAT1 was first demonstrated to associate with metastasis of lung tumor by promoting angiogenesis. Activated vasculature was recently indicated to assist neurogenesis by secreting neurotrophic factor Ang1 (Angiopoietin-1). The purpose of this study is to investigate the potential role of MALAT1 in angiogenesis following traumatic brain injury (TBI). Adult male mice were subjected to controlled cortical impact (CCI) and brain microvascular endothelial cells were exposed to oxygen-glucose deprivation (OGD). MALAT1 RNA levels were quantified by qRT-PCR in different cells of CNS and located by RNA-FISH. Angiogenesis were measured by cell viability, migration assay, tube formation assay in vitro, and immunohistochemistry in vivo. Expression of Angiopoietin-1 was assessed by Western blot. Neurological functions were performed by NSS, Wire grip and MWM tests. Our results indicated that 1) MALAT1 RNA was localized in cerebral endothelium, enhanced by OGD stimuli. 2) Inhibition of MALAT1 by siRNA suppressed angiogenesis, as indicated by endothelial viability, tube formation, migration, and functional vessel density. 3) MALAT1 inhibition further decreased Ang1 expression in the endothelium. 4) Mice with MALAT1 inhibition exhibited worse behavioral performances (NSS, wire grip, Morris water maze), as compared to control. MALAT1 could promote angiogenesis, subsequently contributing to the Ang1 synthesis from active vasculature. It may eventually benefit to functional recovery following TBI.
Collapse
|
|
17
|
Zhang K, Lu WC, Zhang M, Zhang Q, Xian PP, Liu FF, Chen ZY, Kim CS, Wu SX, Tao HR, Wang YZ. Reducing host aldose reductase activity promotes neuronal differentiation of transplanted neural stem cells at spinal cord injury sites and facilitates locomotion recovery. Neural Regen Res 2022; 17:1814-1820. [PMID: 35017443 PMCID: PMC8820702 DOI: 10.4103/1673-5374.330624] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Neural stem cell (NSC) transplantation is a promising strategy for replacing lost neurons following spinal cord injury. However, the survival and differentiation of transplanted NSCs is limited, possibly owing to the neurotoxic inflammatory microenvironment. Because of the important role of glucose metabolism in M1/M2 polarization of microglia/macrophages, we hypothesized that altering the phenotype of microglia/macrophages by regulating the activity of aldose reductase (AR), a key enzyme in the polyol pathway of glucose metabolism, would provide a more beneficial microenvironment for NSC survival and differentiation. Here, we reveal that inhibition of host AR promoted the polarization of microglia/macrophages toward the M2 phenotype in lesioned spinal cord injuries. M2 macrophages promoted the differentiation of NSCs into neurons in vitro. Transplantation of NSCs into injured spinal cords either deficient in AR or treated with the AR inhibitor sorbinil promoted the survival and neuronal differentiation of NSCs at the injured spinal cord site and contributed to locomotor functional recovery. Our findings suggest that inhibition of host AR activity is beneficial in enhancing the survival and neuronal differentiation of transplanted NSCs and shows potential as a treatment of spinal cord injury.
Collapse
Affiliation(s)
- Kun Zhang
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi Province; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Tongji University, Shanghai, China
| | - Wen-Can Lu
- Department of Spine Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong Province, China
| | - Ming Zhang
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Qian Zhang
- Department of Neurology, Hainan Hospital of Chinese PLA General Hospital, Sanya, Hainan Province, China
| | - Pan-Pan Xian
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Fang-Fang Liu
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Zhi-Yang Chen
- Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Chung Sookja Kim
- Faculty of Medicine, Macau University of Science and Technology, Macau Special Administrative Region, China
| | - Sheng-Xi Wu
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| | - Hui-Ren Tao
- Department of Spine Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong Province, China
| | - Ya-Zhou Wang
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi Province, China
| |
Collapse
|
|
18
|
Lukacova N, Kisucka A, Kiss Bimbova K, Bacova M, Ileninova M, Kuruc T, Galik J. Glial-Neuronal Interactions in Pathogenesis and Treatment of Spinal Cord Injury. Int J Mol Sci 2021; 22:13577. [PMID: 34948371 PMCID: PMC8708227 DOI: 10.3390/ijms222413577] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 12/14/2022] Open
Abstract
Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macrophages and microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs. anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlights the time-dependent transformation of reactive microglia and astrocytes into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide suggestions on how to modulate the inflammation and discuss key therapeutic approaches leading to better functional outcome after SCI.
Collapse
Affiliation(s)
- Nadezda Lukacova
- Institute of Neurobiology, Biomedical Research Centre, Slovak Academy of Sciences, Soltesovej 4–6, 040 01 Kosice, Slovakia; (A.K.); (K.K.B.); (M.B.); (M.I.); (T.K.); (J.G.)
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Activation of Three Major Signaling Pathways After Endurance Training and Spinal Cord Injury. Mol Neurobiol 2021; 59:950-967. [PMID: 34811634 PMCID: PMC8857148 DOI: 10.1007/s12035-021-02628-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 10/28/2021] [Indexed: 02/06/2023]
Abstract
We aimed to investigate the effects of endurance training on expression of growth factors (GFs) and stimulation of neurotrophin-dependent signaling pathways (PI3k/Akt, PLCγ/PKC, PLCγ/CAMKII, Ras-Erk1/2 and Rac1-Cdc42) responsible for neuroplasticity, neuroregeneration, survival and growth after spinal cord injury (SCI). Wistar rats were divided into four groups: (i) intact controls; (ii) 6 weeks of endurance training; (iii) SCI; (iv) pre-training + SCI. The animals survived for 6 weeks after SCI. Firstly, endurance training markedly upregulated mRNA expression and protein levels (up to four times) of growth factors (BDNF, GDNF) and their receptors (TrkB, Gfrα) in low thoracic segments (Th8–Th10) compared to levels in untrained animals. Secondly, we found that spontaneous neuroplasticity seen in the SCI alone group was GF-specific and was activated through both PLCγ-PKC and PLC-CAMKII signaling pathways. In addition, training prior to SCI markedly increased the activity of PLCγ-PKC signaling at both transcript and protein levels at and around the lesion site. Similar effects were seen in expression of PI3k/Akt and Ras/Erk1/2 signaling responsible for cell survival and regeneration. Thirdly, rats which underwent physical activity prior to SCI were more active and had significantly better neurological scores at the 14th and 42nd days of survival. These results suggest that regular physical activity could play an important role after SCI, as it maintains increased expression of GFs in spinal cord tissue 6 weeks post-SCI. The BDNF- and/or BDNF + GDNF-dependent signaling pathways were significantly affected in pre-trained SCI animals. In contrast, GDNF-dependent Rac1-Cdc42 signaling was not involved in training-affected SCI response.
Collapse
|
|
20
|
Zeman RJ, Wen X, Ouyang N, Brown AM, Etlinger JD. Role of the Polyol Pathway in Locomotor Recovery and Wallerian Degeneration after Spinal Cord Contusion Injury. Neurotrauma Rep 2021; 2:411-423. [PMID: 34738094 PMCID: PMC8563458 DOI: 10.1089/neur.2021.0018] [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] [Indexed: 01/15/2023] Open
Abstract
Spinal cord contusion injury leads to Wallerian degeneration of axonal tracts, resulting in irreversible paralysis. Contusion injury causes perfusion loss by thrombosis and vasospasm, resulting in spinal cord ischemia. In several tissues, including heart and brain, ischemia activates polyol pathway enzymes—aldose reductase (AR) and sorbitol dehydrogenase (SDH)—that convert glucose to sorbitol and fructose in reactions, causing oxidative stress and tissue loss. We sought to determine whether activation of this pathway, which has been termed glucotoxicity, contributes to tissue loss after spinal cord contusion injury. We tested individual treatments with AR inhibitors (sorbinil or ARI-809), SDH inhibitor (CP-470711), superoxide dismutase mimetic (tempol), or combined sorbinil and tempol. Each treatment significantly increased locomotor recovery and reduced loss of spinal cord tissue in a standard model of spinal cord contusion in rats. Tissue levels of sorbitol and axonal AR (AKR1B10) expression were increased after contusion injury, consistent with activation of the polyol pathway. Sorbinil treatment inhibited the above changes and also decreased axonal swelling and loss, characteristic of Wallerian degeneration. Treatment with tempol induced recovery of locomotor function that was similar in magnitude, but non-additive to sorbinil, suggesting a shared mechanism of action by reactive oxygen species (ROS). Exogenous induction of hyperglycemia further increased injury-induced axonal swelling, consistent with glucotoxicity. Unexpectedly, contusion increased spinal cord levels of glucose, the primary polyol pathway substrate. These results support roles for spinal glucose elevation and tissue glucotoxicity by the polyol pathway after spinal cord contusion injury that results in ROS-mediated axonal degeneration.
Collapse
Affiliation(s)
- Richard J Zeman
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA.,MotoGen Inc., Mount Kisco, New York, USA
| | - Xialing Wen
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA
| | - Nengtai Ouyang
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA
| | - Abraham M Brown
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA
| | - Joseph D Etlinger
- Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, USA.,MotoGen Inc., Mount Kisco, New York, USA
| |
Collapse
|
|
21
|
Kaur H, Erickson A, Moreau R. Divergent regulation of inflammatory cytokines by mTORC1 in THP-1-derived macrophages and intestinal epithelial Caco-2 cells. Life Sci 2021; 284:119920. [PMID: 34478760 DOI: 10.1016/j.lfs.2021.119920] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 08/13/2021] [Accepted: 08/21/2021] [Indexed: 12/12/2022]
Abstract
AIMS The sustained activation of intestinal mechanistic target of rapamycin complex 1 (mTORC1) brought about by repeated mucosal insult or injury has been linked to escalation of gut inflammatory response, which may progress to damage the epithelium if not controlled. This study investigated the role of mTORC1 in the response of macrophage and enterocyte to inflammatory stimuli. MATERIALS AND METHODS We genetically manipulated human THP-1 monocytes and epithelial intestinal Caco-2 cells to generate stable cell lines with baseline, low or high mTORC1 kinase activity. The effects of THP-1 macrophage secretions onto Caco-2 cells were investigated by means of conditioned media transfer experiments. KEY FINDINGS The priming of mTORC1 for activation promoted lipopolysaccharide (LPS)-mediated THP-1 macrophage immune response as evidenced by the stimulation of inflammatory mediators (TNFα, IL-6, IL-8, IL-1β and IL-10). The treatment of THP-1 macrophages with LPS more than the manipulated level of mTORC1 activity of macrophages determined whether cytokine gene expression was induced in Caco-2 cells. LPS carry over was not responsible for the stimulation of Caco-2 cells' cytokine response. Knocking down Raptor in Caco-2 cells or treating Caco-2 cells with rapamycin enhanced Caco-2 TNFα gene expression revealing the anti-inflammatory role of a functional mTORC1 in intestinal epithelial cells exposed to macrophage-derived pro-inflammatory stimuli. SIGNIFICANCE Taken together, mTORC1 differentially impacts the immune responses of THP-1-derived macrophages and Caco-2 epithelial cells when placed in a pro-inflammatory microenvironment.
Collapse
Affiliation(s)
- Harleen Kaur
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Anjeza Erickson
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Régis Moreau
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
| |
Collapse
|
|
22
|
Lu X, Lu F, Yu J, Xue X, Jiang H, Jiang L, Yang Y. Gramine promotes functional recovery after spinal cord injury via ameliorating microglia activation. J Cell Mol Med 2021; 25:7980-7992. [PMID: 34382745 PMCID: PMC8358888 DOI: 10.1111/jcmm.16728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 05/14/2021] [Accepted: 05/31/2021] [Indexed: 11/29/2022] Open
Abstract
In recent years, a large number of studies have reported that neuroinflammation aggravates the occurrence of secondary injury after spinal cord injury. Gramine (GM), a natural indole alkaloid, possesses various pharmacological properties; however, the anti-inflammation property remains unclear. In our study, Gramine was investigated in vitro and in vivo to explore the neuroprotection effects. In vitro experiment, our results suggest that Gramine treatment can inhibit release of pro-inflammatory mediators. Moreover, Gramine prevented apoptosis of PC12 cells which was caused by activated HAPI microglia, and the inflammatory secretion ability of microglia was inhibited by Gramine through NF-κB pathway. The in vivo experiment is that 80 mg/kg Gramine was injected orthotopically to rats after spinal cord injury (SCI). Behavioural and histological analyses demonstrated that Gramine treatment may alleviate microglia activation and then boost recovery of motor function after SCI. Overall, our research has demonstrated that Gramine exerts suppressed microglia activation and promotes motor functional recovery after SCI through NF-κB pathway, which may put forward the prospect of clinical treatment of inflammation-related central nervous diseases.
Collapse
Affiliation(s)
- Xiaolang Lu
- Department of OrthopedicsThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhouChina
- The Second School of MedicineWenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of OrthopedicsWenzhouChina
| | - Fengfeng Lu
- Department of OrthopedicsThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhouChina
- The Second School of MedicineWenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of OrthopedicsWenzhouChina
| | - Jiachen Yu
- Department of OrthopedicsThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhouChina
- The Second School of MedicineWenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of OrthopedicsWenzhouChina
| | - Xinghe Xue
- Department of OrthopedicsThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhouChina
- The Second School of MedicineWenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of OrthopedicsWenzhouChina
| | - Hongyi Jiang
- Department of OrthopedicsThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhouChina
- The Second School of MedicineWenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of OrthopedicsWenzhouChina
| | - Liting Jiang
- Department of OrthopedicsThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhouChina
- The Second School of MedicineWenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of OrthopedicsWenzhouChina
| | - Yang Yang
- Department of OrthopedicsThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityWenzhouChina
- The Second School of MedicineWenzhou Medical UniversityWenzhouChina
- Zhejiang Provincial Key Laboratory of OrthopedicsWenzhouChina
| |
Collapse
|
|
23
|
Cheng P, Xie J, Liu Z, Wang J. Aldose reductase deficiency inhibits LPS-induced M1 response in macrophages by activating autophagy. Cell Biosci 2021; 11:61. [PMID: 33771228 PMCID: PMC8004403 DOI: 10.1186/s13578-021-00576-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/19/2021] [Indexed: 11/10/2022] Open
Abstract
Macrophage M1 polarization mediates inflammatory responses and tissue damage. Recently, aldose reductase (AR) has been shown to play a critical role in M1 polarization in macrophages. However, the underlying mechanisms are unknown. Here, we demonstrated, for the first time, that AR deficiency repressed the induction of inducible nitric oxide synthase in lipopolysaccharide (LPS)-stimulated macrophages via activation of autophagy. This suppression was related to a defect in the inhibitor of nuclear factor κB (NF-κB) kinase (IKK) complex in the classical NF-κB pathway. However, the mRNA levels of IKKβ and IKKγ were not reduced in LPS-treated AR knockout (KO) macrophages, indicating that their proteins were downregulated at the post-transcriptional level. We discovered that LPS stimuli induced the recruitment of more beclin1 and increased autophagosome formation in AR-deficient macrophages. Blocking autophagy through 3-methyladenine and ammonium chloride treatment restored IKKβ and IKKγ protein levels and increased nitric oxide synthase production in LPS-stimulated AR-deficient macrophages. More assembled IKKβ and IKKγ underwent ubiquitination and recruited the autophagic adaptor p62 in LPS-induced AR KO macrophages, promoting their delivery to autophagosomes and lysosomes. Collectively, these findings suggest that AR deficiency is involved in the regulation of NF-κB signaling, and extends the role of selective autophagy in fine-tuned M1 macrophage polarization.
Collapse
Affiliation(s)
- Peng Cheng
- Department of Neurology, Second Naval Hospital of Southern Theater Command (425th Hospital of the People's Liberation Army), Sanya, 572000, China. .,Institute of Neurosciences, Fourth Military Medical University, Xi'an, 710032, China.
| | - Jianwei Xie
- Department of Neurology, Second Naval Hospital of Southern Theater Command (425th Hospital of the People's Liberation Army), Sanya, 572000, China
| | - Zhiyong Liu
- Department of Neurology, Second Naval Hospital of Southern Theater Command (425th Hospital of the People's Liberation Army), Sanya, 572000, China
| | - Jian Wang
- Institute of Neurosciences, Fourth Military Medical University, Xi'an, 710032, China.
| |
Collapse
|
|
24
|
Mi Y, Qi G, Brinton RD, Yin F. Mitochondria-Targeted Therapeutics for Alzheimer's Disease: The Good, the Bad, the Potential. Antioxid Redox Signal 2021; 34:611-630. [PMID: 32143551 PMCID: PMC7891225 DOI: 10.1089/ars.2020.8070] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 03/02/2020] [Indexed: 12/12/2022]
Abstract
Significance: Alzheimer's disease (AD) is the leading cause of dementia. Thus far, 99.6% of clinical trials, including those targeting energy metabolism, have failed to exert disease-modifying efficacy. Altered mitochondrial function and disruption to the brain bioenergetic system have long-been documented as early events during the pathological progression of AD. Recent Advances: While therapeutic approaches that directly promote mitochondrial bioenergetic machinery or eliminate reactive oxygen species have exhibited limited translatability, emerging strategies targeting nonenergetic aspects of mitochondria provide novel therapeutic targets with the potential to modify AD risk and progression. Growing evidence also reveals a critical link between mitochondrial phenotype and neuroinflammation via metabolic reprogramming of glial cells. Critical Issues: Herein, we summarize major classes of mitochondrion-centered AD therapeutic strategies. In addition, the discrepancy in their efficacy when translated from preclinical models to clinical trials is addressed. Key factors that differentiate the responsiveness to bioenergetic interventions, including sex, apolipoprotein E genotype, and cellular diversity in the brain, are discussed. Future Directions: We propose that the future development of mitochondria-targeted AD therapeutics should consider the interactions between bioenergetics and other disease mechanisms, which may require cell-type-specific targeting to distinguish neurons and non-neuronal cells. Moreover, a successful strategy will likely include stratification by metabolic phenotype, which varies by sex and genetic risk profile and dynamically changes throughout the course of disease. As the network of mitochondrial integration expands across intracellular and systems level biology, assessment of intended, the good, versus unintended consequences, the bad, will be required to reach the potential of mitochondrial therapeutics.
Collapse
Affiliation(s)
- Yashi Mi
- Center for Innovation in Brain Science, University of Arizona Health Sciences, Tucson, Arizona, USA
| | - Guoyuan Qi
- Center for Innovation in Brain Science, University of Arizona Health Sciences, Tucson, Arizona, USA
| | - Roberta Diaz Brinton
- Center for Innovation in Brain Science, University of Arizona Health Sciences, Tucson, Arizona, USA
- Department of Pharmacology, College of Medicine Tucson, Tucson, Arizona, USA
- Department of Neurology, College of Medicine Tucson, Tucson, Arizona, USA
- Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, Arizona, USA
| | - Fei Yin
- Center for Innovation in Brain Science, University of Arizona Health Sciences, Tucson, Arizona, USA
- Department of Pharmacology, College of Medicine Tucson, Tucson, Arizona, USA
- Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, Arizona, USA
| |
Collapse
|
|
25
|
Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries. Biomolecules 2021; 11:biom11010099. [PMID: 33451166 PMCID: PMC7828679 DOI: 10.3390/biom11010099] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 12/13/2022] Open
Abstract
Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these.
Collapse
|
|
26
|
Kaur H, Moreau R. Curcumin steers THP-1 cells under LPS and mTORC1 challenges toward phenotypically resting, low cytokine-producing macrophages. J Nutr Biochem 2020; 88:108553. [PMID: 33220404 DOI: 10.1016/j.jnutbio.2020.108553] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/07/2020] [Accepted: 11/02/2020] [Indexed: 12/13/2022]
Abstract
The persistent activation of intestinal mechanistic target of rapamycin complex 1 (mTORC1) triggered by mucosal stress has been linked to deregulation of the gut immune response resulting in intestinal inflammation and cell death. The present study investigated the regulatory properties of food-derived mTORC1 modulators, curcumin, and piperine, toward the polarization of stimulated macrophages and the differentiation of monocytes at two mTORC1 activity levels (baseline and elevated). To that end, we created stable human THP-1 monocytes exhibiting normal or constitutively active mTORC1. Curcumin or its combination with piperine, but not piperine alone, suppressed mTORC1 kinase activity, curtailed lipopolysaccharide-mediated inflammatory response of THP-1 macrophages, and repressed macrophage activation by inhibiting signaling pathways involved in M1 (mTORC1) and M2 (mTORC2 and cAMP response element binding protein) polarization. The effects of piperine in the curcumin/piperine combination were modest overall, indicating it was curcumin that modulated differentiating monocytes into acquiring a M0 macrophage phenotype characterized by low inflammatory cytokine output.
Collapse
Affiliation(s)
- Harleen Kaur
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Régis Moreau
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
| |
Collapse
|
|
27
|
Wei X, Jin XH, Meng XW, Hua J, Ji FH, Wang LN, Yang JP. Platelet-rich plasma improves chronic inflammatory pain by inhibiting PKM2-mediated aerobic glycolysis in astrocytes. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1456. [PMID: 33313201 PMCID: PMC7723564 DOI: 10.21037/atm-20-6502] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Astrocytes are highly glycolytic cells that play a crucial role in chronic pain. Recently it has been found that inflammation and metabolism are related to the inflammatory stimuli closely that cause cellular metabolic changes. Pyruvate kinase M2 (PKM2) is a critical metabolic kinase in aerobic glycolysis or the Warburg effect. Besides, it also plays a crucial role in cell proliferation and signal transduction, but its role in astrocytes is still unclear. Methods The chronic inflammatory pain model was set up by intraplantar injection of complete Freund’s adjuvant (CFA) in Sprague Dawley (SD) rats as well as the cell model was constructed by lipopolysaccharide-treated primary astrocytes. Von Frey filament stimulation was used to continuously observe the changes of pain behavior in rats after modeling. Then, immunofluorescence staining and Western blot tests were used to observe the expression levels of glial fibrillary acidic protein (GFAP), pyruvate kinase (PKM2), signal transducers and activators of transcription 3 (STAT3) and high mobility group box-1 protein (HMGB1). After that, specific kits measured lactate contents. Finally, we observed the platelet-rich plasma’s (PRP) effect on mechanical hyperalgesia in rats with inflammatory pain induced by CFA and its effect on related signal molecules. Results We found that in the CFA-induced inflammatory pain model, astrocytes were significantly activated, GFAP was increased, PKM2 was significantly up-regulated, and the glycolytic product lactate was increased. Also, intrathecal injection of PRP increased the pain threshold, inhibited the activation of astrocytes, and decreased the expression of PKM2 and aerobic glycolysis; in LPS-activated primary astrocytes as an in vitro model, we found PKM2 translocation activationSTAT3 signaling resulted in sustained activation of astrocyte marker GFAP, and the expression level and localization of p-STAT3 were correlated with PKM2. PRP could inhibit the activation of astrocytes, reduce the expression of PKM2 and the expression levels of glycolysis and GFAP, GLUT1, and p-STAT3 in astrocytes. Conclusions Our findings suggest PKM2 not only plays a glycolytic role in astrocytes, but also plays a crucial role in astrocyte-activated signaling pathways, and PRP attenuates CFA induced inflammatory pain by inhibiting aerobic glycolysis in astrocytes, providing a new therapeutic target for the treatment of inflammatory pain.
Collapse
Affiliation(s)
- Xiang Wei
- Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiao-Hong Jin
- Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiao-Wen Meng
- Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jie Hua
- Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fu-Hai Ji
- Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Li-Na Wang
- Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jian-Ping Yang
- Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
|
28
|
Khayami R, Hashemi SR, Kerachian MA. Role of aldo-keto reductase family 1 member B1 (AKR1B1) in the cancer process and its therapeutic potential. J Cell Mol Med 2020; 24:8890-8902. [PMID: 32633024 PMCID: PMC7417692 DOI: 10.1111/jcmm.15581] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/21/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
The role of aldo‐keto reductase family 1 member B1 (AKR1B1) in cancer is not totally clear but growing evidence is suggesting to have a great impact on cancer progression. AKR1B1 could participate in a complicated network of signalling pathways, proteins and miRNAs such as mir‐21 mediating mechanisms like inflammatory responses, cell cycle, epithelial to mesenchymal transition, cell survival and apoptosis. AKR1B1 has been shown to be mostly overexpressed in cancer. This overexpression has been associated with inflammatory mediators including nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB), cell cycle mediators such as cyclins and cyclin‐dependent kinases (CDKs), survival proteins and pathways like mammalian target of rapamycin (mTOR) and protein kinase B (PKB) or AKT, and other regulatory factors in response to reactive oxygen species (ROS) and prostaglandin synthesis. In addition, inhibition of AKR1B1 has been shown to mostly have anti‐cancer effects. Several studies have also suggested that AKR1B1 inhibition as an adjuvant therapy could render tumour cells more sensitive to anti‐cancer therapy or alleviate the adverse effects of therapy. AKR1B1 could also be considered as a potential cancer diagnostic biomarker since its promoter has shown high levels of methylation. Although pre‐clinical investigations on the role of AKR1B1 in cancer and the application of its inhibitors have shown promising results, the lack of clinical studies on AKR1B1 inhibitors has hampered the use of these drugs to treat cancer. Thus, there is a need to conduct more clinical studies on the application of AKR1B1 inhibitors as adjuvant therapy on different cancers.
Collapse
Affiliation(s)
- Reza Khayami
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyyed Reza Hashemi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Amin Kerachian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Genetics Research Unit, Reza Radiotherapy and Oncology Center, Mashhad, Iran
| |
Collapse
|
|
29
|
Jiang CT, Wu WF, Deng YH, Ge JW. Modulators of microglia activation and polarization in ischemic stroke (Review). Mol Med Rep 2020; 21:2006-2018. [PMID: 32323760 PMCID: PMC7115206 DOI: 10.3892/mmr.2020.11003] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 02/06/2020] [Indexed: 12/16/2022] Open
Abstract
Ischemic stroke is one of the leading causes of mortality and disability worldwide. However, there is a current lack of effective therapies available. As the resident macrophages of the brain, microglia can monitor the microenvironment and initiate immune responses. In response to various brain injuries, such as ischemic stroke, microglia are activated and polarized into the proinflammatory M1 phenotype or the anti‑inflammatory M2 phenotype. The immunomodulatory molecules, such as cytokines and chemokines, generated by these microglia are closely associated with secondary brain damage or repair, respectively, following ischemic stroke. It has been shown that M1 microglia promote secondary brain damage, whilst M2 microglia facilitate recovery following stroke. In addition, autophagy is also reportedly involved in the pathology of ischemic stroke through regulating the activation and function of microglia. Therefore, this review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke. The effects of autophagy on microglia polarization in ischemic stroke were also reviewed. Finally, future research areas of ischemic stroke and the implications of the current knowledge for the development of novel therapeutics for ischemic stroke were identified.
Collapse
Affiliation(s)
- Cheng-Ting Jiang
- Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Wan-Feng Wu
- Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Yi-Hui Deng
- Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| | - Jin-Wen Ge
- Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China
| |
Collapse
|
|
30
|
Lu E, Wang Q, Li S, Chen C, Wu W, Xu YXZ, Zhou P, Tu W, Lou X, Rao G, Yang G, Jiang S, Zhou K. Profilin 1 knockdown prevents ischemic brain damage by promoting M2 microglial polarization associated with the RhoA/ROCK pathway. J Neurosci Res 2020; 98:1198-1212. [PMID: 32291804 DOI: 10.1002/jnr.24607] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Revised: 02/11/2020] [Accepted: 02/18/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Ermei Lu
- Department of Physical Medicine and Rehabilitation The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China
- Integrative & Optimized Medicine Research Center Institute for Acupuncture and Rehabilitation Wenzhou Medical University Wenzhou China
- Department of Pharmacy The First People's Hospital of Wenling The Affiliated Wenling Hospital of Wenzhou Medical University Wenling China
| | - Qian Wang
- Department of Pharmacy The First People's Hospital of Wenling The Affiliated Wenling Hospital of Wenzhou Medical University Wenling China
| | - Shengcun Li
- Department of Physical Medicine and Rehabilitation The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China
- Integrative & Optimized Medicine Research Center Institute for Acupuncture and Rehabilitation Wenzhou Medical University Wenzhou China
| | - Caiming Chen
- Department of Pharmacy The First People's Hospital of Wenling The Affiliated Wenling Hospital of Wenzhou Medical University Wenling China
| | - Weibo Wu
- Department of Pharmacy The First People's Hospital of Wenling The Affiliated Wenling Hospital of Wenzhou Medical University Wenling China
| | - Yang Xin Zi Xu
- Department of Physiology and Pathophysiology University of Manitoba Winnipeg MB Canada
| | - Peng Zhou
- Department of Anatomy Wenzhou Medical University Wenzhou China
| | - Wenzhan Tu
- Department of Physical Medicine and Rehabilitation The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China
- Integrative & Optimized Medicine Research Center Institute for Acupuncture and Rehabilitation Wenzhou Medical University Wenzhou China
| | - Xinfa Lou
- Integrative & Optimized Medicine Research Center Institute for Acupuncture and Rehabilitation Wenzhou Medical University Wenzhou China
| | - Gaofeng Rao
- Department of Rehabilitation Medicine The First People's Hospital of Wenling The Affiliated Wenling Hospital of Wenzhou Medical University Wenling China
| | - Guanhu Yang
- Department of Physical Medicine and Rehabilitation The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China
- Integrative & Optimized Medicine Research Center Institute for Acupuncture and Rehabilitation Wenzhou Medical University Wenzhou China
| | - Songhe Jiang
- Department of Physical Medicine and Rehabilitation The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China
- Integrative & Optimized Medicine Research Center Institute for Acupuncture and Rehabilitation Wenzhou Medical University Wenzhou China
| | - Kecheng Zhou
- Department of Physical Medicine and Rehabilitation The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China
- Integrative & Optimized Medicine Research Center Institute for Acupuncture and Rehabilitation Wenzhou Medical University Wenzhou China
| |
Collapse
|
|
31
|
Li K, Liang Z, Zhang J, Zuo X, Sun J, Zheng Q, Song J, Ding T, Hu X, Wang Z. Attenuation of the inflammatory response and polarization of macrophages by photobiomodulation. Lasers Med Sci 2020; 35:1509-1518. [PMID: 32065300 DOI: 10.1007/s10103-019-02941-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 12/22/2019] [Indexed: 12/11/2022]
Abstract
In spinal cord injury (SCI), inflammation is a major mediator of damage and loss of function and is regulated primarily by the bone marrow-derived macrophages (BMDMs). Photobiomodulation (PBM) or low-level light stimulation is known to have anti-inflammatory effects and has previously been used in the treatment of SCI, although its precise cellular mechanisms remain unclear. In the present study, the effect of PBM at 810 nm on classically activated BMDMs was evaluated to investigate the mechanisms underlying its anti-inflammatory effects. BMDMs were cultured and irradiated (810 nm, 2 mW/cm2) following stimulation with lipopolysaccharide and interferon-γ. CCK-8 assay, 2',7'-dichlorofluorescein diacetate assay, and ELISA and western blot analysis were performed to measure cell viability, reactive oxygen species production, and inflammatory marker production, respectively. PBM irradiation of classically activated macrophages significantly increased the cell viability and inhibited reactive oxygen species generation. PBM suppressed the expression of a marker of classically activated macrophages, inducible nitric oxide synthase; decreased the mRNA expression and secretion of pro-inflammatory cytokines, tumor necrosis factor alpha, and interleukin-1 beta; and increased the secretion of monocyte chemotactic protein 1. Exposure to PBM likewise significantly reduced the expression and phosphorylation of NF-κB p65 in classically activated BMDMs. Taken together, these results suggest that PBM can successfully modulate inflammation and polarization in classically activated BMDMs. The present study provides a theoretical basis to support wider clinical application of PBM in the treatment of SCI.
Collapse
Affiliation(s)
- Kun Li
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zhuowen Liang
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jiawei Zhang
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaoshuang Zuo
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jiakai Sun
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qiao Zheng
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jiwei Song
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Tan Ding
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xueyu Hu
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Zhe Wang
- Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
| |
Collapse
|
|
32
|
Excess salt intake promotes M1 microglia polarization via a p38/MAPK/AR-dependent pathway after cerebral ischemia in mice. Int Immunopharmacol 2020; 81:106176. [PMID: 32044667 DOI: 10.1016/j.intimp.2019.106176] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 11/28/2019] [Accepted: 12/30/2019] [Indexed: 11/24/2022]
Abstract
A high salt diet (HSD) is among the most important risk factors for many diseases. One mechanism by which HSD aggravates cerebral ischemic injury is independent of blood pressure changes. The direct role of HSD in inflammation after cerebral ischemia is unclear. In this research, after twenty-one days of being fed a high salt diet, permanent focal ischemia was induced in mice via operation. At 12 h and 1, 3 and 5 days postischemia, the effects of HSD on the lesion volume, microglia polarization, aldose reductase (AR) expression, and inflammatory processes were analyzed. We report that in mice, surplus dietary salt promotes inflammation and increases the activation of classical lipopolysaccharide (LPS)-induced microglia/macrophages (M1). This effect depends on the expression of the AR protein in activated microglia after permanent middle cerebral artery ligation (pMCAL) in HSD mice. The administration of either the AR inhibitor Epalrestat or a p38-neutralizing antibody blocked the polarization of microglia and alleviated stroke injury. In conclusion, HSD promotes polarization in pro-inflammatory M1 microglia by upregulating the expression of the AR protein via p38/MAPK, thereby exacerbating the development of ischemia stroke.
Collapse
|
|
33
|
Chen Z, Guo H, Lu Z, Sun K, Jin Q. Hyperglycemia aggravates spinal cord injury through endoplasmic reticulum stress mediated neuronal apoptosis, gliosis and activation. Biomed Pharmacother 2019; 112:108672. [PMID: 30784940 DOI: 10.1016/j.biopha.2019.108672] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 01/29/2019] [Accepted: 02/05/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hyperglycemia has been shown to influence prognostic outcome of spinal cord injury (SCI). However, the corresponding mechanism is not very clear. AIM This study is expected to explore the role of endoplasmic reticulum (ER) stress in hyperglycemia aggravated SCI. METHODS Hyperglycemia was established in rats by intraperitoneal (i.p.) injection of streptozotocin. SCI was performed at the T10 of spinal cord through weight dropping. ER stress was suppressed by oral gavage of 4-PBA. ER stress, histological change of the injured spinal cords, neuronal apoptosis, demyelination, glial proliferation, inflammatory factor production, blood-spinal cord barrier (BSCB) permeability, TJ (Occludin, Claudin5) and AJ (β-catenin, P120) protein degradation, and locomotor recovery were determined using western blotting, immunohistochemistry, HE staining, Evan's Blue assay, BBB scores and inclined plane test, respectively. In vitro, rat spinal cord neurons cells (RSCNCs) and cerebral microvascular endothelial cells (RCMECs) were stimulated with high glucose (HG) and/or thapsigargin (TG). The effects of HG and/or TG on RSCNCs apoptosis, and AJ and TJ expression by RCMECs were evaluated with flow cytometry and western blotting, respectively. RESULTS Hyperglycemic rats exhibited enhanced ER stress, increased neuronal apoptosis, aggravated demyelination, increased glial proliferation and inflammatory factors secretion, more serious BSCB disruption and disturbed locomotor recovery. ER stress inhibition alleviated hyperglycemia induced adverse effect on neuronal apoptosis and BSCB permeability, whereas showed little influence on glial activation and inflammation. CONCLUSION ER stress was aggravated in hyperglycemic rats after SCI, and subsequently promoted neuronal apoptosis and BSCB disruption in rats.
Collapse
Affiliation(s)
- Zhirong Chen
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Haohui Guo
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Zhidong Lu
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Kening Sun
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China
| | - Qunhua Jin
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China.
| |
Collapse
|
|
34
|
Significant changes in circular RNA in the mouse cerebral cortex around an injury site after traumatic brain injury. Exp Neurol 2018; 313:37-48. [PMID: 30529438 DOI: 10.1016/j.expneurol.2018.12.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 10/30/2018] [Accepted: 12/04/2018] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVE Circular RNA (circRNA) is an important type of non-coding RNA that has not been widely researched in traumatic brain injury (TBI). The present study aimd to detect the altered circRNA expression around an injury site in the mouse cerebral cortex after TBI and explore its potential functions. METHOD C57BL/6 mice were used to construct a controlled cortical impact (CCI) model to simulate TBI. At 24 h post-TBI, the cortex around the injury site was collected, and the total RNA was extracted to perform RNA sequencing (RNA-seq). The differentially expressed circRNAs were determined according to the following criteria: |log2(fold change)| > 1, P < .05 and FDR < 0.05. Among them, circRNA chr8_87,859,283-87,904,548 was preliminarily explored to determine its function. RESULTS A total of 8036 altered circRNAs were discovered, and among them, 16 were significantly changed (5 up-regulated and 11 down-regulated). The circRNA chr8_87,859,283-87,904,548 significantly increased by approximately 4 times in the cerebral cortex around the injury site after TBI and promoted neuro-inflammation through increasing the CXCR2 protein by sponging mmu-let-7a-5p. As a result, the increased circRNA chr8_87,859,283-87,904,548 blocked the restoration of neurological function after TBI. CONCLUSION Many circRNAs are significantly up-regulated or down-regulated in the traumatic cerebral penumbra cortex after TBI. Among them, the circRNA chr8_87,859,283-87,904,548 potentially plays a pro-inflammatory role, which may have a deleterious effect on neurological restoration after TBI. .
Collapse
|
|
35
|
Bian G, Yu C, Liu L, Fang C, Chen K, Ren P, Zhang Q, Liu F, Zhang K, Xue Q, Xiang J, Guo H, Song J, Zhao Y, Wu W, Chung SK, Sun R, Ju G, Wang J. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling. Sci Signal 2018; 11:11/553/eaat1470. [DOI: 10.1126/scisignal.aat1470] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. We identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Our results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.
Collapse
|
|
36
|
Fumagalli M, Lombardi M, Gressens P, Verderio C. How to reprogram microglia toward beneficial functions. Glia 2018; 66:2531-2549. [PMID: 30195261 PMCID: PMC6585737 DOI: 10.1002/glia.23484] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/13/2018] [Accepted: 06/13/2018] [Indexed: 12/13/2022]
Abstract
Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro‐regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders.
Collapse
Affiliation(s)
- Marta Fumagalli
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti, 9 -20133, Milan, Italy
| | | | - Pierre Gressens
- PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, 1141 Paris, France.,Centre for the Developing Brain, Department of Perinatal Health and Imaging, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, United Kingdom
| | - Claudia Verderio
- IRCCS Humanitas, via Manzoni 56, 20089, Rozzano, Italy.,CNR Institute of Neuroscience, via Vanvitelli 32, 20129 Milan, Italy
| |
Collapse
|
|
37
|
Riemann L, Younsi A, Scherer M, Zheng G, Skutella T, Unterberg AW, Zweckberger K. Transplantation of Neural Precursor Cells Attenuates Chronic Immune Environment in Cervical Spinal Cord Injury. Front Neurol 2018; 9:428. [PMID: 29951030 PMCID: PMC6008566 DOI: 10.3389/fneur.2018.00428] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 05/22/2018] [Indexed: 11/13/2022] Open
Abstract
Inflammation after traumatic spinal cord injury (SCI) is non-resolving and thus still present in chronic injury stages. It plays a key role in the pathophysiology of SCI and has been associated with further neurodegeneration and development of neuropathic pain. Neural precursor cells (NPCs) have been shown to reduce the acute and sub-acute inflammatory response after SCI. In the present study, we examined effects of NPC transplantation on the immune environment in chronic stages of SCI. SCI was induced in rats by clip-compression of the cervical spinal cord at the level C6-C7. NPCs were transplanted 10 days post-injury. The functional outcome was assessed weekly for 8 weeks using the Basso, Beattie, and Bresnahan scale, the CatWalk system, and the grid walk test. Afterwards, the rats were sacrificed, and spinal cord sections were examined for M1/M2 macrophages, T lymphocytes, astrogliosis, and apoptosis using immunofluorescence staining. Rats treated with NPCs had compared to the control group significantly fewer pro-inflammatory M1 macrophages and reduced immunodensity for inducible nitric oxide synthase (iNOS), their marker enzyme. Anti-inflammatory M2 macrophages were rarely present 8 weeks after the SCI. In this model, the sub-acute transplantation of NPCs did not support survival and proliferation of M2 macrophages. Post-traumatic apoptosis, however, was significantly reduced in the NPC group, which might be explained by the altered microenvironment following NPC transplantation. Corresponding to these findings, reactive astrogliosis was significantly reduced in NPC-transplanted animals. Furthermore, we could observe a trend toward smaller cavity sizes and functional improvement following NPC transplantation. Our data suggest that transplantation of NPCs following SCI might attenuate inflammation even in chronic injury stages. This might prevent further neurodegeneration and could also set a stage for improved neuroregeneration after SCI.
Collapse
Affiliation(s)
- Lennart Riemann
- Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Alexander Younsi
- Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Moritz Scherer
- Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Guoli Zheng
- Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Skutella
- Department of Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany
| | - Andreas W Unterberg
- Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Klaus Zweckberger
- Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany
| |
Collapse
|
|
38
|
Cumaoğlu A, Yerer MB. The Effects of Aldose Reductase Inhibitor Quercetin and Monochloropivaloylquercetin in Amyloid β Peptide (1–42) Induced Neuroinflammation in Microglial Cells. Nat Prod Commun 2018. [DOI: 10.1177/1934578x1801300611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Microglial over-activation plays a crucial roles during neuroinflammation. Aldose reductase (AR) is one of the enzymes that has been linked to inflammatory processes in several diseases. Therefore, inhibition of AR is considered as an important strategy to reduce inflammation. In the present study, Quercetin (Q) and monochloropivaloylquercetin (MCPQ) showed potent inhibition on AR expression and anti-neuroinflammatory effects in Amyloid β (Aβ) peptide (1–42) induced inflammatory process by inhibiting expression of inflammatory mediators from microglial cells. Furthermore, ablation of AR caused a significant reduction on COX2 expression in Aβ-induced neuroinflammation. Q and MCPQ suppressed COX2 mRNA and protein expression, which further resulted in downstream inhibition of prostaglandin E2 (PGE2) release in Aβ-induced neuroinflammatory process. Additionally, Aβ treatment resulted in activation of Mitogen Activated Protein Kinase (MAPK) and increased translocation of Nuclear Factor Kappa B (NFκB). Q and Sorbinil significantly reduced the activation of MAPK, at the same time Q, MCPQ and sorbinil decreased nuclear translocation of NFκB and diminished tumor necrosis factor (TNF)-α release in Aβ-induced neuroinflammation. The results suggested that AR is a probable target for treatment of neuroinflammation as well as Q and MCPQ could be effective agents for treating or preventing inflammation-related neurodegenerative diseases by AR inhibition.
Collapse
Affiliation(s)
- Ahmet Cumaoğlu
- Department of Biochemistry, Faculty of Pharmacy, Erciyes University, Kayseri, 38039, Turkey
| | - Mükerrem Betül Yerer
- Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, 38039, Turkey
| |
Collapse
|
|
39
|
Chen S, Ye J, Chen X, Shi J, Wu W, Lin W, Lin W, Li Y, Fu H, Li S. Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3. J Neuroinflammation 2018; 15:150. [PMID: 29776446 PMCID: PMC5960086 DOI: 10.1186/s12974-018-1193-6] [Citation(s) in RCA: 215] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 05/08/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Microglial polarization with M1/M2 phenotype shifts and the subsequent neuroinflammatory responses are vital contributing factors for spinal cord injury (SCI)-induced secondary injury. Nuclear factor-κB (NF-κB) is considered the central transcription factor of inflammatory mediators, which plays a crucial role in microglial activation. Lysine acetylation of STAT1 seems necessary for NF-kB pathway activity, as it is regulated by histone deacetylases (HDACs). There have been no studies that have explained if HDAC inhibition by valproic acid (VPA) affects the NF-κB pathway via acetylation of STAT1 dependent of HDAC activity in the microglia-mediated central inflammation following SCI. We investigated the potential molecular mechanisms that focus on the phenotypic transition of microglia and the STAT1-mediated NF-κB acetylation after a VPA treatment. METHODS The Basso-Beattie-Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, and Nissl staining were employed to determine the neuroprotective effects of VPA treatment after SCI. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (INF)-γ was used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of VPA treatment. Immunofluorescent staining and Western blot analysis were used to detect HDAC3 nuclear translocation, activity, and NF-κB signaling pathway activation to evaluate the effects of VPA treatment. The impact of STAT1 acetylation on NF-kB pathway and the interaction between STAT1 and NF-kB were assessed to evaluate anti-inflammation effects of VPA treatment and also whether these effects were dependent on a STAT1/NF-κB pathway to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after SCI. RESULTS The results showed that the VPA treatment promoted the phenotypic shift of microglia from M1 to M2 phenotype and inhibited microglial activation, thus reducing the SCI-induced inflammatory factors. The VPA treatment upregulation of the acetylation of STAT1/NF-κB pathway was likely caused by the HDAC3 translocation to the nucleus and activity. These results indicated that the treatment with the VPA suppressed the expression and the activity of HDAC3 and enhanced STAT1, as well as NF-κB p65 acetylation following a SCI. The acetylation status of NF-kB p65 and the complex with NF-κB p65 and STAT1 inhibited the NF-kB p65 transcriptional activity and attenuated the microglia-mediated central inflammatory response following SCI. CONCLUSIONS These results suggested that the VPA treatment attenuated the inflammatory response by modulating microglia polarization through STAT1-mediated acetylation of the NF-κB pathway, dependent of HDAC3 activity. These effects led to neuroprotective effects following SCI.
Collapse
Affiliation(s)
- Shoubo Chen
- Department of Orthopaedics, The Second Affiliated Hospital, Fujian Medical Universityz, Quanzhou, 362000, Fujian Province, China
| | - Jingfang Ye
- Department of nursing faculty, Quanzhou Medical College, Quanzhou, 362000, Fujian Province, China
| | - Xiangrong Chen
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, 362000, Fujian Province, China.
| | - Jinnan Shi
- Department of Orthopaedics, The Second Affiliated Hospital, Fujian Medical Universityz, Quanzhou, 362000, Fujian Province, China
| | - Wenhua Wu
- Department of Orthopaedics, The Second Affiliated Hospital, Fujian Medical Universityz, Quanzhou, 362000, Fujian Province, China
| | - Wenping Lin
- Department of Orthopaedics, The Second Affiliated Hospital, Fujian Medical Universityz, Quanzhou, 362000, Fujian Province, China
| | - Weibin Lin
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Yasong Li
- Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, 362000, Fujian Province, China
| | - Huangde Fu
- Department of Neurosurgery, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi Province, China
| | - Shun Li
- Department of Neurosurgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan Province, China.
| |
Collapse
|
|
40
|
Wang B, Liu S, Fan B, Xu X, Chen Y, Lu R, Xu Z, Liu X. PKM2 is involved in neuropathic pain by regulating ERK and STAT3 activation in rat spinal cord. J Headache Pain 2018; 19:7. [PMID: 29349661 PMCID: PMC5773456 DOI: 10.1186/s10194-018-0836-4] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 01/08/2018] [Indexed: 01/10/2023] Open
Abstract
Background Pyruvate kinase isozymes M2 (PKM2), as a member of pyruvate kinase family, plays a role of glycolytic enzyme in glucose metabolism. It also functions as protein kinase in cell proliferation, signaling, immunity, and gene transcription. In this study, the role of PKM2 in neuropathic pain induced by chronic constriction injury (CCI) was investigated. Methods Rats were randomly grouped to establish CCI models. PKM2, extracellular regulated protein kinases (EKR), p-ERK, signal transducers and activators of transcription (STAT3), p-STAT3, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and p-PI3K/AKT proteins expression in spinal cord was examined by Western blot analysis. Cellular location of PKM2 was examined by immunofluorescence. Knockdown of PKM2 was achieved by intrathecal injection of specific small interfering RNA (siRNA). Von Frey filaments and radiant heat tests were performed to determine mechanical allodynia and thermal hyperalgesia respectively. Lactate and adenosine triphosphate (ATP) contents were measured by specific kits. Tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels were detected by ELISA kits. Results CCI markedly increased PKM2 level in rat spinal cord. Double immunofluorescent staining showed that PKM2 co-localized with neuron, astrocyte, and microglia. Intrathecal injection of PKM2 siRNA not only attenuated CCI-induced ERK and STAT3 activation, but also attenuated mechanical allodynia and thermal hyperalgesia induced by CCI. However, PKM2 siRNA failed to inhibit the activation of AKT. In addition, PKM2 siRNA significantly suppressed the production of lactate and pro-inflammatory mediators. Conclusion Our findings demonstrate that inhibiting PKM2 expression effectively attenuates CCI-induced neuropathic pain and inflammatory responses in rats, possibly through regulating ERK and STAT3 signaling pathway.
Collapse
Affiliation(s)
- Binbin Wang
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Siyuan Liu
- Department of Anesthesiology, Nantong Maternity and Child Health Hospital, Nantong, Jiangsu, 226018, China
| | - Bingbing Fan
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, Department of Medical Imaging, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xingguo Xu
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Yonglin Chen
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Rongxiang Lu
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Zhongling Xu
- Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
| | - Xiaojuan Liu
- Department of Pathogen Biology, Medical College, Nantong University, Nantong, Jiangsu, 2266001, China.
| |
Collapse
|
|
41
|
Amelogenin induces M2 macrophage polarisation via PGE2/cAMP signalling pathway. Arch Oral Biol 2017; 83:241-251. [DOI: 10.1016/j.archoralbio.2017.08.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 06/30/2017] [Accepted: 08/08/2017] [Indexed: 11/22/2022]
|
|
42
|
Zhong J, Jiang L, Huang Z, Zhang H, Cheng C, Liu H, He J, Wu J, Darwazeh R, Wu Y, Sun X. The long non-coding RNA Neat1 is an important mediator of the therapeutic effect of bexarotene on traumatic brain injury in mice. Brain Behav Immun 2017; 65:183-194. [PMID: 28483659 DOI: 10.1016/j.bbi.2017.05.001] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 05/03/2017] [Accepted: 05/03/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Bexarotene treatments exert neuroprotective effects on mice following traumatic brain injury (TBI). The present study aims to investigate the potential roles of the long noncoding RNA Neat1 in the neuroprotective effects of bexarotene. MATERIALS AND METHODS Adult male C57BL/6J mice (n=80) and newborn mice (within 24h after birth) (n=20) were used to generate a "controlled cortical impact" (CCI) model and harvest primary cortex neurons, respectively. The HT22 cell line and the BV2 cell line were cultured under "normal" or "oxygen/glucose-deprived" (OGD) conditions. The relationship between RXR-α and the Neat1 promoter was clarified using ChIP-qPCR and dual-luciferase reporter gene assays. The mRNA alterations induced by Neat1 knockdown were measured using next-generation RNA sequencing. Proteins were captured by Neat1, pulled down and subjected to mass spectrometry. The neurological severity score, rotarod test and water maze test were employed to measure the animals' motor and cognitive functions. RESULTS Bexarotene prominently up-regulated the Neat1 level in an RXR-α-dependent manner. Neat1 knockdown induced significant changes in mRNA expression, and the altered mRNAs were involved in many biological processes, including synapse formation and axon guidance. In primary neurons, Neat1 knockdown inhibited and Neat1 over-expression prompted axon elongation. Multiple proteins, including Pidd1, were captured by Neat1. Neat1 inhibited cell apoptosis and restricted inflammation by capturing Pidd1. The in vitro anti-apoptotic and anti-inflammatory effects of Neat1 were further confirmed in C57BL/6 mice, which resulted in better motor and cognitive function after TBI. CONCLUSION Bexarotene up-regulates the lncRNA Neat1, which inhibits apoptosis and inflammation, thereby resulting in better functional recovery in mice after TBI.
Collapse
Affiliation(s)
- Jianjun Zhong
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Li Jiang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China.
| | - Zhijian Huang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Hongrong Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Chongjie Cheng
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Han Liu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Junchi He
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Jingchuan Wu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Rami Darwazeh
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Yue Wu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China
| | - Xiaochuan Sun
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, China.
| |
Collapse
|
|
43
|
Astaxanthin acts via LRP-1 to inhibit inflammation and reverse lipopolysaccharide-induced M1/M2 polarization of microglial cells. Oncotarget 2017; 8:69370-69385. [PMID: 29050210 PMCID: PMC5642485 DOI: 10.18632/oncotarget.20628] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 08/17/2017] [Indexed: 12/17/2022] Open
Abstract
Microglia become activated during neuroinflammation and produce neurotoxic and neurotrophic factors, depending on whether they acquire M1 proinflammatory or M2 anti-inflammatory phenotypes. Astaxanthin (ATX), a natural carotenoid, has anti-inflammatory and neuroprotective effects. We investigated whether ATX could reverse M1/M2 polarization and suppress neuroinflammation via low-density lipoprotein receptor-related protein-1 (LRP-1). We observed increased expression of M1 (TNF-α, IL-1β, and CD86) and decreased expression of M2 (Arg-1, IL-10, and CD206) markers in BV2 microglial cells stimulated with lipopolysaccharide (LPS). These alterations were reversed by pretreating the cells with ATX. Activation of the NF-κB and JNK pathways was observed upon LPS stimulation, which was reversed by ATX. ATX-induced M2 polarization was attenuated by inhibition of NF-κB and JNK. Pretreatment of LPS-stimulated BV2 cells with ATX resulted in increased LRP-1 expression. The addition of receptor-associated protein, an LRP-1 antagonist, ameliorated ATX-induced inactivation of NF-κB and JNK signaling, and M2 polarization. ATX promotes M2 polarization to suppress neuroinflammation via LRP-1 by inhibiting NF-κB and JNK signaling. This novel mechanism may suppress neuroinflammation in diseases such as Alzheimer’s disease.
Collapse
|
|
44
|
Zhao J, Wang L, Li Y. Electroacupuncture Alleviates the Inflammatory Response via Effects on M1 and M2 Macrophages after Spinal Cord Injury. Acupunct Med 2017; 35:224-230. [PMID: 28077367 DOI: 10.1136/acupmed-2016-011107] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2016] [Indexed: 01/09/2023]
Abstract
Background Macrophages/microglia are important effector cells at the site of spinal cord injury (SCI). M1-type macrophages facilitate innate immunity to remove foreign microbes and wound debris from the injury site. M2-type macrophages exhibit tissue repair properties and attenuate production of pro-inflammatory cytokines. Regulation of the polarisation of M1/M2 macrophages may affect the inflammatory response in SCI and may be related to neurotrophin-3 (NT-3). Electroacupuncture (EA) at GV acupuncture points can be used as an adjuvant therapy for SCI. Aim To investigate the effects of EA on Basso, Beattie and Bresnahan (BBB) functional evaluation and inflammatory cytokines (tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-10), and on the proportions of M1/M2 macrophages, and to provide a greater understanding of the mechanisms underlying the potential clinical treatment of SCI. Methods A rat SCI model was induced by spinal segment transection at T10 in 16 Sprague-Dawley rats. A further eight rats were included as a Control group. Ten surviving SCI model rats were divided into two groups (n=5 each): an SCI group that remained untreated; and an SCI+EA group that received EA at GV6 and GV9. Results EA improved BBB scores, inhibited the proportion of M1 macrophages and TNF-α, IL-1β and IL-6 levels, and downregulated the M1 marker CD86. By contrast, EA enhanced IL-10, the proportion of M2 macrophages and upregulated the M2 marker CD206 and NT-3 expression. Conclusions EA had a positive impact on SCI model rats. This may be related to the neuroprotective effect of NT-3, which may increase the polarisation of M2 microglia/macrophages.
Collapse
Affiliation(s)
- Jiagui Zhao
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Likui Wang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| | - Yuanhai Li
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
| |
Collapse
|
|
45
|
Song GJ, Suk K. Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases. Front Aging Neurosci 2017; 9:139. [PMID: 28555105 PMCID: PMC5430023 DOI: 10.3389/fnagi.2017.00139] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 04/25/2017] [Indexed: 01/06/2023] Open
Abstract
Microglia are the resident innate immune cells of the central nervous system that mediate brain homeostasis maintenance. Microglia-mediated neuroinflammation is a hallmark shared by various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Numerous studies have shown microglial activation phenotypes to be heterogeneous; however, these microglial phenotypes can largely be categorized as being either M1 or M2 type. Although the specific classification of M1 and M2 functionally polarized microglia remains a topic for debate, the use of functional modulators of microglial phenotypes as potential therapeutic approaches for the treatment of neurodegenerative diseases has garnered considerable attention. This review discusses M1 and M2 microglial phenotypes and their relevance in neurodegenerative disease models, as described in recent literature. The modulation of microglial polarization toward the M2 phenotype may lead to development of future therapeutic and preventive strategies for neuroinflammatory and neurodegenerative diseases. Thus, we focus on recent studies of microglial polarization modulators, with a particular emphasis on the small-molecule compounds and their intracellular target proteins.
Collapse
Affiliation(s)
- Gyun Jee Song
- BK21 Plus KNU Biomedical Convergence Program, Department of Pharmacology, Brain Science & Engineering Institute, School of Medicine, Kyungpook National UniversityDaegu, South Korea
| | - Kyoungho Suk
- BK21 Plus KNU Biomedical Convergence Program, Department of Pharmacology, Brain Science & Engineering Institute, School of Medicine, Kyungpook National UniversityDaegu, South Korea
| |
Collapse
|
|
46
|
Low-level laser facilitates alternatively activated macrophage/microglia polarization and promotes functional recovery after crush spinal cord injury in rats. Sci Rep 2017; 7:620. [PMID: 28377600 PMCID: PMC5428709 DOI: 10.1038/s41598-017-00553-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 03/03/2017] [Indexed: 12/14/2022] Open
Abstract
Macrophages and resident microglia play an import role in the secondary neuroinflammation response following spinal cord injury. Reprogramming of macrophage/microglia polarization is an import strategy for spinal cord injury restoration. Low-level laser therapy (LLLT) is a noninvasive treatment that has been widely used in neurotrauma and neurodegenerative diseases. However, the influence of low-level laser on polarization of macrophage/microglia following spinal cord injury remains unknown. The present study applied low-level laser therapy on a crush spinal cord injury rat model. Using immunofluorescence, flow cytometry, RT-qPCR, and western blot assays, we found that low-level laser therapy altered the polarization state to a M2 tendency. A greater number of neurons survived in the pare injury site, which was accompanied by higher BBB scores in the LLLT group. Furthermore, low-level laser therapy elevated expression of interleukin 4 (IL-4) and interleukin 13 (IL-13). Results from this study show that low-level laser therapy has the potential for reducing inflammation, regulating macrophage/microglia polarization, and promoting neuronal survival. These beneficial effects demonstrate that low-level laser therapy may be an effective candidate for clinical treatment of spinal cord injury.
Collapse
|
|
47
|
Song L, Pei L, Yao S, Wu Y, Shang Y. NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies. Front Cell Neurosci 2017; 11:63. [PMID: 28337127 PMCID: PMC5343070 DOI: 10.3389/fncel.2017.00063] [Citation(s) in RCA: 339] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2016] [Accepted: 02/22/2017] [Indexed: 12/14/2022] Open
Abstract
Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases.
Collapse
Affiliation(s)
- Limin Song
- Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Lei Pei
- Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Shanglong Yao
- Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Yan Wu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - You Shang
- Department of Critical Care Medicine, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| |
Collapse
|
|
48
|
Kong X, Gao J. Macrophage polarization: a key event in the secondary phase of acute spinal cord injury. J Cell Mol Med 2016; 21:941-954. [PMID: 27957787 PMCID: PMC5387136 DOI: 10.1111/jcmm.13034] [Citation(s) in RCA: 135] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 09/29/2016] [Indexed: 01/18/2023] Open
Abstract
Acute spinal cord injury (SCI) has become epidemic in modern society. Despite advances made in the understanding of the pathogenesis and improvements in early recognition and treatment, it remains a devastating event, often producing severe and permanent disability. SCI has two phases: acute and secondary. Although the acute phase is marked by severe local and systemic events such as tissue contusion, ischaemia, haemorrhage and vascular damage, the outcome of SCI are mainly influenced by the secondary phase. SCI causes inflammatory responses through the activation of innate immune responses that contribute to secondary injury, in which polarization‐based macrophage activation is a hallmarker. Macrophages accumulated within the epicentre and the haematoma of the injured spinal cord play a significant role in this inflammation. Depending on their phenotype and activation status, macrophages may initiate secondary injury mechanisms and/or promote CNS regeneration and repair. When it comes to therapies for SCI, very few can be performed in the acute phase. However, as macrophage activation and polarization switch are exquisitely sensitive to changes in microenvironment, some trials have been conducted to modulate macrophage polarization towards benefiting the recovery of SCI. Given this, it is important to understand how macrophages and SCI interrelate and interact on a molecular pathophysiological level. This review provides a comprehensive overview of the immuno‐pathophysiological features of acute SCI mainly from the following perspectives: (i) the overview of the pathophysiology of acute SCI, (ii) the roles of macrophage, especially its polarization switch in acute SCI, and (iii) newly developed neuroprotective therapies modulating macrophage polarization in acute SCI.
Collapse
Affiliation(s)
- Xiangyi Kong
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.,Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Harvard University, Boston, MA, USA
| | - Jun Gao
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
49
|
Chen CH, Chen NF, Feng CW, Cheng SY, Hung HC, Tsui KH, Hsu CH, Sung PJ, Chen WF, Wen ZH. A Coral-Derived Compound Improves Functional Recovery after Spinal Cord Injury through Its Antiapoptotic and Anti-Inflammatory Effects. Mar Drugs 2016; 14:md14090160. [PMID: 27598175 PMCID: PMC5039531 DOI: 10.3390/md14090160] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 08/22/2016] [Accepted: 08/26/2016] [Indexed: 12/24/2022] Open
Abstract
Background: Our previous in vitro results demonstrated that 11-dehydrosinulariolide significantly reduced 6-hydroxydopamine-induced cytotoxicity and apoptosis in a human neuroblastoma cell line, SH-SY5Y, and suppressed the expression of inducible NO synthase (iNOS) and cyclooxygenase 2 in lipopolysaccharide-stimulated macrophage cells. The neuroprotective and anti-inflammatory effects of 11-dehydrosinulariolide may be suitable for treating spinal cord injury (SCI). Methods: In the present study, Wistar rats were pretreated with 11-dehydrosinulariolide or saline through intrathecal injection after a thoracic spinal cord contusion injury induced using a New York University (NYU) impactor. The apoptotic cells were assessed using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expression and localization of proinflammatory, apoptosis-associated and cell survival-related pathway proteins were examined through immunoblotting and immunohistochemistry. Results: 11-Dehydrosinulariolide attenuated SCI-induced cell apoptosis by upregulating the antiapoptotic protein Bcl-2 and cell survival-related pathway proteins p-Akt and p-ERK, 8 h after SCI. Furthermore, the transcription factor p-CREB, which regulates Bcl-2 expression, was upregulated after 11-dehydrosinulariolide treatment. On day 7 after SCI, 11-dehydrosinulariolide exhibited an anti-inflammatory effect, attenuating SCI-induced upregulation of the inflammatory proteins iNOS and tumor necrosis factor-α. 11-Dehydrosinulariolide also induced an increase in the expression of arginase-1 and CD206, markers of M2 microglia, in the injured spinal cord on day 7 after SCI. Thus, the anti-inflammatory effect of 11-dehydrosinulariolide may be related to the promotion of an alternative pathway of microglia activation. Conclusion: The results show that 11-dehydrosinulariolide exerts antiapoptotic effects at 8 h after SCI and anti-inflammatory effects at 7 days after SCI. We consider that this compound may be a promising therapeutic agent for SCI.
Collapse
Affiliation(s)
- Chun-Hong Chen
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
- Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei 11529, Taiwan.
| | - Nan-Fu Chen
- Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
| | - Chien-Wei Feng
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
- Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei 11529, Taiwan.
| | - Shu-Yu Cheng
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
- Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei 11529, Taiwan.
| | - Han-Chun Hung
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
- Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei 11529, Taiwan.
| | - Kuan-Hao Tsui
- Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan.
- Department of Obstetrics and Gynecology and Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
- Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung County 90741, Taiwan.
| | - Chi-Hsin Hsu
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
| | - Ping-Jyun Sung
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
- National Museum of Marine Biology & Aquarium, Pingtung 94450, Taiwan.
- Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 94450, Taiwan.
| | - Wu-Fu Chen
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
| | - Zhi-Hong Wen
- Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
| |
Collapse
|
|
50
|
Sinomenine enhances microglia M2 polarization and attenuates inflammatory injury in intracerebral hemorrhage. J Neuroimmunol 2016; 299:28-34. [PMID: 27725118 DOI: 10.1016/j.jneuroim.2016.08.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 06/30/2016] [Accepted: 08/08/2016] [Indexed: 12/13/2022]
Abstract
Microglia polarization plays a vital role in brain inflammatory injury following intracerebral hemorrhage (ICH). Previous studies have shown that sinomenine possesses potential immunoregulatory capabilities. However, microglia polarization's exact mechanisms in ICH remain uncertain. Therefore, we examined the role of sinomenine on microglia polarization and brain inflammation following ICH. For the experiment, autologous blood models were constructed in C57/BL6 mice. Markers of classically activated (M1) and alternatively activated (M2) microglia were detected by real-time polymerase chain reaction, immunofluorescence, and flow cytometry. Microglial toxicity was assessed using MTT and FACS assays. In addition, the neurological deficit and cerebral water content of ICH mice were also observed. Sinomenine attenuated M1 markers while promoting M2 markers of microglia. Sinomenine also protected hippocampal neurons from indirect toxicity mediated by ICH-treated microglia. Additionally, administration of sinomenine inhibited matrix metalloproteinase (MMP) 3/9 expression, cerebral water content, and neurological deficit. Therefore, sinomenine protected brain function following ICH, perhaps via M2 microglia phenotype induction and MMP 3/9 inhibition. This result suggests that sinomenine is a promising therapeutical strategy in ICH.
Collapse
|