Neurobiol Dis|Olga V. Chechneva团队指出CD11c+小胶质细胞与EAE临床进展关联

2022年8月4日 0条评论 265次阅读 0人点赞

最新细胞功能及机制文献分享

多发性硬化症（MS）是一种慢性自身免疫性脱髓鞘疾病，临床症状具有高度可变性。在大多数情况下，MS在后期会转变为不可逆的神经功能进行性衰退，实验性自身免疫性脑脊髓炎（EAE）是MS的动物模型。目前，对MS进展的潜在机制仍然知之甚少。2021年11月6日，美国加州大学戴维斯分校医学院生物化学与分子医学系Olga V. Chechneva团队在Neurobiology of Disease上发表了题为“Reduction in CD11c⁺ microglia correlates with clinical progression in chronic experimental autoimmune demyelination”的研究论文。在本研究中，团队确定了慢性EAE进展的病理性特征，并表明CD11c⁺小胶质细胞可能是调节自身免疫性脱髓鞘中免疫细胞实质浸润的关键。

临床结果显示，MS的特征是髓鞘丢失、慢性炎症和轴突变性，在80%的患者中，MS表现为复发缓解型（RRMS）。越来越多的证据表明，CD11c⁺小胶质细胞在疾病中具有神经保护功能，其过表达缓解了EAE临床残疾，并减轻了铜宗诱导的脱髓鞘。研究表明，炎症的关键调节因子是MAPK14（p38α），而在MS患者的活动性和慢性病变中p38α表达均上调，并且CD11c⁺经典树突细胞（cDC）中的p38α信号传导又是MS和EAE中未成熟T细胞向TH17表型分化所必需的，其中还涉及IL-6–STAT3信号通路。同时，p38α也是cDC在过继EAE转移中重激活髓鞘诱发TH17表型细胞所必需的，其药理抑制或在骨髓细胞中的敲除均改善了雌性小鼠EAE临床症状和炎症。

基于此，团队在此项研究中，再次构建了雌性小鼠EAE模型，结果发现，具有轻度EAE的小鼠在免疫后30天容易出现EAE进展，且EAE进展的特征是分散的聚结实质浸润。与C57BL/6野生型（WT）小鼠的临床进展相比，在EAE进展小鼠模型中，CD11c⁺小胶质细胞明显减少，并在未出现EAE进展的小鼠模型中发现，CD11c⁺小胶质细胞与星形胶质细胞和脉管系统相关，换句话说，CD11c⁺小胶质细胞可与保留在血管周围空间内的神经胶质限制和免疫细胞的星形胶质细胞过程形成接触。最后，团队还发现，p38α（炎症反应的关键调节因子）信号传导具有性别依赖性差异，即在CD11c启动子驱动的p38α KO雌性小鼠中选择性减少CD11c⁺小胶质细胞与EAE进展速度增加相关。

《Neurobiol Dis|Olga V. Chechneva团队指出CD11c+小胶质细胞与EAE临床进展关联》

图 CD11c⁺小胶质细胞在胶质细胞限制处与星形胶质细胞形成接触。

期刊及DOI号

Neurobiol Dis. 2021 Nov 6.

doi: 10.1016/j.nbd.2021.105556.

题目

Reduction in CD11c⁺ microglia correlates with clinical progression in chronic experimental autoimmune demyelination

摘要

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease with high variability of clinical symptoms. In most cases MS appears as a relapsing-remitting disease course that at a later stage transitions into irreversible progressive decline of neurologic function. The mechanisms underlying MS progression remain poorly understood. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS. Here we demonstrate that mice that develop mild EAE after immunization with myelin oligodendrocyte glycoprotein 35–55 are prone to undergo clinical progression around 30days after EAE induction. EAE progression was associated with reduction in CD11c+ microglia and dispersed coalescent parenchymal infiltration. We found sex-dependent differences mediated by p38α signaling, a key regulator of inflammation. Selective reduction of CD11c⁺ microglia in female mice with CD11c-promoter driven p38α knockout (KO) correlated with increased rate of EAE progression. In protected animals, we found CD11c⁺ microglia forming contacts with astrocyte processes at the glia limitans and immune cells retained within perivascular spaces. Together, our study identified pathological hallmarks of chronic EAE progression and suggests that CD11c⁺ microglia may regulate immune cell parenchymal infiltration in autoimmune demyelination.

关键词：CD11c⁺ microglia；EAE progression；CNS infiltration；p38α sexual dimorphism；Glia limitans