Genetic ablation of steroid receptor coactivator-3 promotes PPAR-beta-mediated alternative activation of microglia in experimental autoimmune encephalomyelitis.
Genetic ablation of steroid receptor coactivator-3 promotes PPAR-beta-mediated alternative activation of microglia in experimental autoimmune encephalomyelitis.
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DOI：
10.1002/glia.20975
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发表时间：
2010-06
期刊：
影响因子：
6.2
通讯作者：
Zhang, Yanyun
中科院分区：
文献类型：
--
作者：
Xiao, Yichuan;Xu, Jingwei;Wang, Shu;Mao, Chaoming;Jin, Min;Ning, Guang;Xu, Jianming;Zhang, Yanyun
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质代谢。在本研究中，通过分析SRC-3缺陷（SRC-3−/−）小鼠的疾病进展，研究了SRC-3在以中枢神经系统炎症性脱髓鞘为特征的实验性自身免疫性脑脊髓炎（EAE）中的潜在作用。我们发现SRC-3缺乏显著减轻了EAE的疾病严重程度，并减少了炎症浸润和脱髓鞘。然而，这些影响不是由外周T细胞反应的抑制引起的，而是由CNS中过氧化物酶体增殖物激活受体(PPAR)-β的上调表达引起的，这在SRC-3−/−小鼠中诱导了小胶质细胞的替代激活状态。这些交替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和调节素如C1qa和C1qb，抑制中枢神经系统炎症。此外，小胶质细胞替代激活通过增加sc -3−/−小鼠白质中少突胶质细胞前体（OPCs）的积累和脊髓中髓磷脂基因的表达升高，促进髓磷脂再生。我们的研究结果建立了脂质代谢调节与免疫功能之间的联系，并且SRC-3或PPAR-β的表达调节有望在MS和其他神经退行性疾病中具有治疗模式。
Steroid receptor coactivator-3 (SRC-3) has been demonstrated to regulate lipid metabolism by inhibiting adipocyte differentiation. In the present study, the potential role of SRC-3 in experimental autoimmune encephalomyelitis (EAE), which characterized by inflammatory demyelination in 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 up-regulated expression of peroxisome proliferator-activated receptor (PPAR)-β in CNS, which induced an alternative activation state of microglia in SRC-3−/− mice. These alternatively activated microglia inhibited CNS inflammation through inhibition of pro-inflammatory cytokines and chemokines, such as TNF-α, IFN-γ, CCL2, CCL3, CCL5 and CXCL10, as well as up-regulation 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 (OPCs) 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-β may hopefully has therapeutic modality in MS and possibly other neurodegenerative diseases.
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DOI：
10.1073/pnas.0808207105
发表时间：
2008-11-04
影响因子：
11.1
作者：
Coste, Agnes;Louet, Jean-Francois;Auwerx, Johan
通讯作者：
Auwerx, Johan
影响因子：
5.3
作者：
Girard, C;Bemelmans, AP;Lachapelle, F
通讯作者：
Lachapelle, F
影响因子：
4.4
作者：
Gocke, Anne R.;Hussain, Rehana Z.;Racke, Michael K.
通讯作者：
Racke, Michael K.
影响因子：
82.9
作者：
Heppner, FL;Greter, M;Aguzzi, A
通讯作者：
Aguzzi, A
DOI：
10.4049/jimmunol.0804192
发表时间：
2009-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Li B;Reynolds JM;Stout RD;Bernlohr DA;Suttles J
通讯作者：
Suttles J