最近，国际重要学术期刊Glia在线发表了中科院上海生命科学研究院健康所张雁云研究组博士生肖意传、徐经纬等研究人员关于脂代谢的调节影响神经再生修复和神经机体免疫功能的新发现。
脂代谢调节的紊乱会导致多种疾病的发生，但是其对神经再生修复和神经免疫功能的影响目前还尚不清楚。内固醇受体辅激活因子（SRC-3）是机体脂代谢调节中重要转录因子，研究人员发现，SRC3基因敲除小鼠较野生型小鼠瘦小，且其脂代谢水平较高。利用SRC-3基因敲除小鼠构建实验性自身免疫性脑脊髓炎（EAE）模型，发现基因敲除小鼠表现出对EAE诱导的耐受。其原因是SRC3基因敲除促进了炎症条件下中枢神经系统（CNS）中小胶质细胞处于一种非经典的激活状态，这些非经典激活的小胶质细胞通过上调抗炎症细胞因子IL-10的表达来对抗EAE诱导引起的CNS炎症，并促进了CNS少突胶质细胞诱导的髓鞘再生。进一步分析相关的机制，发现这种非经典激活的小胶质细胞是由于SRC3基因敲除诱导了炎症条件下CNS中PPAR-b的升高引起的，也调节了神经干细胞的活化、增殖和分化。在此研究中，首次揭示了CNS小胶质细胞的非经典激活形式及抗炎症效应及其相关分子机制，也发现了调节影响神经干细胞活化、增殖分化及再生修复病理损伤的重要代谢分子信号途径，为神经干细胞再生修复损伤提供了新的思路。
该研究受到科技部重大科学研究计划、重大新药创制专项、国家自然科学，上海市科委，上海市教委等基金的支持。
推荐原文出处：
Glia doi:10.1002/glia.20975
Genetic ablation of steroid receptor coactivator-3 promotes PPAR--mediated alternative activation of microglia in experimental autoimmune encephalomyelitis
Yichuan Xiao 1, Jingwei Xu 1, Shu Wang 2 3, Chaoming Mao 1, Min Jin 1, Guang Ning 2 3, Jianming Xu 4, Yanyun Zhang 1 *
1Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences " SJTUSM, Shanghai, China
2Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences " SJTUSM, Shanghai, China
3Department of Endocrinology and Metabolism, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, SJTUSM, Shanghai, China
4Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
Steroid receptor coactivator-3 (SRC-3) has been demonstrated to regulate lipid metabolism by inhibiting adipocyte differentiation. In this study, the potential role of SRC-3 in experimental autoimmune encephalomyelitis (EAE), which characterized by inflammatory demyelination in central nervous system (CNS), was examined by analyzing disease progression in SRC-3-deficient (SRC-3-/-) mice. We found that SRC-3 deficiency significantly attenuated the disease severity of EAE along with decreased inflammatory infiltration and demyelination. However, these effects are not caused by inhibition of peripheral T cell response, but by upregulated expression of peroxisome proliferator-activated receptor (PPAR)- in CNS, which induced an alternative activation state of microglia in SRC-3-/- mice. These alternatively activated microglia inhibited CNS inflammation through inhibition of proinflammatory cytokines and chemokines, such as TNF-, IFN-, CCL2, CCL3, CCL5, and CXCL10, as well as upregulation of anti-inflammatory cytokine IL-10 and opsonins, such as C1qa and C1qb. Moreover, microglia alternative activation promoted myelin regeneration through increased accumulation of oligodendrocyte precursors in white matter and elevated expression of myelin genes in the spinal cords of SRC-3-/- mice. Our results build up a link between lipid metabolic regulation and immune functions, and the modulation of the expression of SRC-3 or PPAR- may hopefully has therapeutic modality in MS and possibly other neurodegenerative diseases.
