Shanghai 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 200025, China.
Glia. 2010 Jun;58(8):932-42. doi: 10.1002/glia.20975.
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)-beta 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-alpha, IFN-gamma, 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-beta may hopefully has therapeutic modality in MS and possibly other neurodegenerative diseases.
类固醇受体共激活因子-3（SRC-3）已被证明通过抑制脂肪细胞分化来调节脂代谢。在这项研究中，通过分析 SRC-3 缺陷（SRC-3(-/-)）小鼠的疾病进展，研究了 SRC-3 在实验性自身免疫性脑脊髓炎（EAE）中的潜在作用，EAE 的特征是中枢神经系统（CNS）的炎症性脱髓鞘。我们发现，SRC-3 缺乏显着减轻了 EAE 的疾病严重程度，同时减少了炎症浸润和脱髓鞘。然而，这些作用不是通过抑制外周 T 细胞反应引起的，而是由于 CNS 中过氧化物酶体增殖物激活受体（PPAR）-β的表达上调引起的，该作用诱导了 SRC-3(-/-)小鼠中小胶质细胞的替代激活状态。这些替代激活的小胶质细胞通过抑制促炎细胞因子和趋化因子（如 TNF-α、IFN-γ、CCL2、CCL3、CCL5 和 CXCL10）以及上调抗炎细胞因子 IL-10 和调理素（如 C1qa 和 C1qb）来抑制 CNS 炎症。此外，小胶质细胞的替代激活通过增加白质中少突胶质细胞前体的积累和上调 SRC-3(-/-)小鼠脊髓中的髓鞘基因表达来促进髓鞘再生。我们的研究结果在脂质代谢调节和免疫功能之间建立了联系，调节 SRC-3 或 PPAR-β的表达可能有望成为 MS 及其他神经退行性疾病的治疗方法。
