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      Activation of HCA2 regulates microglial responses to alleviate neurodegeneration in LPS-induced in vivo and in vitro models

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          Abstract

          Background

          Previous studies have shown a close association between an altered immune system and Parkinson's disease (PD). Neuroinflammation inhibition may be an effective measure to prevent PD. Recently, numerous reports have highlighted the potential of hydroxy-carboxylic acid receptor 2 (HCA2) in inflammation-related diseases. Notably, the role of HCA2 in neurodegenerative diseases is also becoming more widely known. However, its role and exact mechanism in PD remain to be investigated. Nicotinic acid (NA) is one of the crucial ligands of HCA2, activating it. Based on such findings, this study aimed to examine the effect of HCA2 on neuroinflammation and the role of NA-activated HCA2 in PD and its underlying mechanisms.

          Methods

          For in vivo studies, 10-week-old male C57BL/6 and HCA2 −/− mice were injected with LPS in the substantia nigra (SN) to construct a PD model. The motor behavior of mice was detected using open field, pole-climbing and rotor experiment. The damage to the mice's dopaminergic neurons was detected using immunohistochemical staining and western blotting methods. In vitro, inflammatory mediators (IL-6, TNF-α, iNOS and COX-2) and anti-inflammatory factors (Arg-1, Ym-1, CD206 and IL-10) were detected using RT-PCR, ELISA and immunofluorescence. Inflammatory pathways (AKT, PPARγ and NF-κB) were delineated by RT-PCR and western blotting. Neuronal damage was detected using CCK8, LDH, and flow cytometry assays.

          Results

          HCA2 −/− increases mice susceptibility to dopaminergic neuronal injury, motor deficits, and inflammatory responses. Mechanistically, HCA2 activation in microglia promotes anti-inflammatory microglia and inhibits pro-inflammatory microglia by activating AKT/PPARγ and inhibiting NF-κB signaling pathways. Further, HCA2 activation in microglia attenuates microglial activation-mediated neuronal injury. Moreover, nicotinic acid (NA), a specific agonist of HCA2, alleviated dopaminergic neuronal injury and motor deficits in PD mice by activating HCA2 in microglia in vivo.

          Conclusions

          Niacin receptor HCA2 modulates microglial phenotype to inhibit neurodegeneration in LPS-induced in vivo and in vitro models.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12974-023-02762-5.

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          Most cited references45

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          Microglial M1/M2 polarization and metabolic states.

          Microglia are critical nervous system-specific immune cells serving as tissue-resident macrophages influencing brain development, maintenance of the neural environment, response to injury and repair. As influenced by their environment, microglia assume a diversity of phenotypes and retain the capability to shift functions to maintain tissue homeostasis. In comparison with peripheral macrophages, microglia demonstrate similar and unique features with regards to phenotype polarization, allowing for innate immunological functions. Microglia can be stimulated by LPS or IFN-γ to an M1 phenotype for expression of pro-inflammatory cytokines or by IL-4/IL-13 to an M2 phenotype for resolution of inflammation and tissue repair. Increasing evidence suggests a role of metabolic reprogramming in the regulation of the innate inflammatory response. Studies using peripheral immune cells demonstrate that polarization to an M1 phenotype is often accompanied by a shift in cells from oxidative phosphorylation to aerobic glycolysis for energy production. More recently, the link between polarization and mitochondrial energy metabolism has been considered in microglia. Under these conditions, energy demands would be associated with functional activities and cell survival and thus, may serve to influence the contribution of microglia activation to various neurodegenerative conditions. This review examines the polarization states of microglia and their relationship to mitochondrial metabolism. Additional supporting experimental data are provided to demonstrate mitochondrial metabolic shifts in primary microglia and the BV-2 microglia cell line induced under LPS (M1) and IL-4/IL-13 (M2) polarization.
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            Inflammation and immune dysfunction in Parkinson disease

            Parkinson disease (PD) is a progressive neurodegenerative disease that affects peripheral organs as well as the central nervous system and involves a fundamental role of neuroinflammation in its pathophysiology. Neurohistological and neuroimaging studies support the presence of ongoing and end-stage neuroinflammatory processes in PD. Moreover, numerous studies of peripheral blood and cerebrospinal fluid from patients with PD suggest alterations in markers of inflammation and immune cell populations that could initiate or exacerbate neuroinflammation and perpetuate the neurodegenerative process. A number of disease genes and risk factors have been identified as modulators of immune function in PD and evidence is mounting for a role of viral or bacterial exposure, pesticides and alterations in gut microbiota in disease pathogenesis. This has led to the hypothesis that complex gene-by-environment interactions combine with an ageing immune system to create the ‘perfect storm’ that enables the development and progression of PD. We discuss the evidence for this hypothesis and opportunities to harness the emerging immunological knowledge from patients with PD to create better preclinical models with the long-term goal of enabling earlier identification of at-risk individuals to prevent, delay and more effectively treat the disease. This Review from Tansey and colleagues explores how an ageing immune system, host genetics and exposure to various environmental stressors combine to promote the development of Parkinson disease.
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              Neuroinflammation in Parkinson's disease: a target for neuroprotection?

              Parkinson's disease is characterised by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra. Despite intensive research, the cause of the neuronal loss in Parkinson's disease is poorly understood. Neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration. In this Review, we describe the evidence for neuroinflammatory processes from post-mortem and in vivo studies in Parkinson's disease. We further identify the cellular and molecular events associated with neuroinflammation that are involved in the degeneration of dopaminergic neurons in animal models of the disease. Overall, available data support the importance of non-cell-autonomous pathological mechanisms in Parkinson's disease, which are mostly mediated by activated glial and peripheral immune cells. This cellular response to neurodegeneration triggers deleterious events (eg, oxidative stress and cytokine-receptor-mediated apoptosis), which might eventually lead to dopaminergic cell death and hence disease progression. Finally, we highlight possible therapeutic strategies (including immunomodulatory drugs and therapeutic immunisation) aimed at downregulating these inflammatory processes that might be important to slow the progression of Parkinson's disease.
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                Author and article information

                Contributors
                m13144303829@163.com
                fushoupeng@jlu.edu.cn
                yebj871781602@163.com
                Wanghf9919@mails.jlu.edu.cn
                heyuan9919@mails.jlu.edu.cn
                lizhe9920@mails.jlu.edu.cn
                lijie9920@mails.jlu.edu.cn
                gaoxy9916@mails.jlu.edu.cn
                ccldf@163.com
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                29 March 2023
                29 March 2023
                2023
                : 20
                : 86
                Affiliations
                [1 ]GRID grid.64924.3d, ISNI 0000 0004 1760 5735, College of Animal Science, , Jilin University, ; Changchun, China
                [2 ]GRID grid.64924.3d, ISNI 0000 0004 1760 5735, College of Veterinary Medicine, , Jilin University, ; Changchun, China
                Article
                2762
                10.1186/s12974-023-02762-5
                10053461
                36991440
                02897ef4-efb2-4888-a353-8618d847f01d
                © The Author(s) 2023

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 10 June 2022
                : 10 March 2023
                Funding
                Funded by: Fundamental Research Funds for the Central Universities under Grant
                Award ID: 2021JCKT-06
                Award Recipient :
                Funded by: National Natural Science Foundation of China
                Award ID: 31772547
                Award Recipient :
                Funded by: College Students Innovation and Entrepreneurship Training Program of Jilin University
                Award ID: S202210183609, X202210183635
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2023

                Neurosciences
                parkinson's disease,hca2,neuroinflammation,nicotinic acid
                Neurosciences
                parkinson's disease, hca2, neuroinflammation, nicotinic acid

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