最近,，國際重要學(xué)術(shù)期刊Glia在線發(fā)表了中科院上海生命科學(xué)研究院健康所張雁云研究組博士生肖意傳,、徐經(jīng)緯等研究人員關(guān)于脂代謝的調(diào)節(jié)影響神經(jīng)再生修復(fù)和神經(jīng)機體免疫功能的新發(fā)現(xiàn)。
脂代謝調(diào)節(jié)的紊亂會導(dǎo)致多種疾病的發(fā)生,，但是其對神經(jīng)再生修復(fù)和神經(jīng)免疫功能的影響目前還尚不清楚,。內(nèi)固醇受體輔激活因子（SRC-3）是機體脂代謝調(diào)節(jié)中重要轉(zhuǎn)錄因子，研究人員發(fā)現(xiàn),，SRC3基因敲除小鼠較野生型小鼠瘦小,，且其脂代謝水平較高。利用SRC-3基因敲除小鼠構(gòu)建實驗性自身免疫性腦脊髓炎（EAE）模型,，發(fā)現(xiàn)基因敲除小鼠表現(xiàn)出對EAE誘導(dǎo)的耐受,。其原因是SRC3基因敲除促進了炎癥條件下中樞神經(jīng)系統(tǒng)（CNS）中小膠質(zhì)細胞處于一種非經(jīng)典的激活狀態(tài)，這些非經(jīng)典激活的小膠質(zhì)細胞通過上調(diào)抗炎癥細胞因子IL-10的表達來對抗EAE誘導(dǎo)引起的CNS炎癥,，并促進了CNS少突膠質(zhì)細胞誘導(dǎo)的髓鞘再生,。進一步分析相關(guān)的機制，發(fā)現(xiàn)這種非經(jīng)典激活的小膠質(zhì)細胞是由于SRC3基因敲除誘導(dǎo)了炎癥條件下CNS中PPAR-b的升高引起的,，也調(diào)節(jié)了神經(jīng)干細胞的活化,、增殖和分化。在此研究中,，首次揭示了CNS小膠質(zhì)細胞的非經(jīng)典激活形式及抗炎癥效應(yīng)及其相關(guān)分子機制,，也發(fā)現(xiàn)了調(diào)節(jié)影響神經(jīng)干細胞活化、增殖分化及再生修復(fù)病理損傷的重要代謝分子信號途徑,，為神經(jīng)干細胞再生修復(fù)損傷提供了新的思路,。
該研究受到科技部重大科學(xué)研究計劃、重大新藥創(chuàng)制專項,、國家自然科學(xué),，上海市科委,，上海市教委等基金的支持。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
