美国国立卫生研究院Dorian B. McGavern团队近期取得重要工作进展，他们研究发现单核细胞来源的IL-6对小胶质细胞进行编程以重建受损的脑血管系统。相关研究成果2023年5月29日在线发表于《自然—免疫学》杂志上。

据介绍，脑血管损伤（CVI）是由感染、损伤、中风、神经退行性变和自身免疫性疾病引起的常见病理。CVI的快速解决需要协调的先天免疫反应。

研究人员探究了中枢神经系统浸润性单核细胞如何编程驻留的小胶质细胞，介导脑出血后血管生成和脑血管修复的相关机制。在人类中风脑损伤的半影中，研究人员鉴定了一个表达血管内皮生长因子a的小胶质细胞亚群。这些细胞被称为“修复相关小胶质细胞”（RAM），也在CVI和共表达白细胞介素（IL）-6Ra的啮齿动物模型中观察到。

在IL-6敲除或缺乏小胶质细胞IL-6Ra表达的小鼠中没有发生脑血管修复，单细胞转录组学分析显示，在缺乏IL-6信号的情况下，RAM编程有缺陷。浸润性CCR2⁺单核细胞是CVI后IL-6的主要来源，并且需要赋予小胶质细胞增殖和促血管生成的特性。在缺乏IL-6或炎性单核细胞的情况下，错误的RAM编程导致脑血管修复不良、神经元破坏和持续的神经功能缺损，这些都是通过外源性IL-6给药恢复的。

总之，这些数据为单核细胞如何指导小胶质细胞修复受损的脑血管系统，并促进损伤后的功能恢复提供了分子和细胞基础。

附：英文原文

Title: Monocyte-derived IL-6 programs microglia to rebuild damaged brain vasculature

Author: Choi, Bo-Ran, Johnson, Kory R., Maric, Dragan, McGavern, Dorian B.

Issue&Volume: 2023-05-29

Abstract: Cerebrovascular injury (CVI) is a common pathology caused by infections, injury, stroke, neurodegeneration and autoimmune disease. Rapid resolution of a CVI requires a coordinated innate immune response. In the present study, we sought mechanistic insights into how central nervous system-infiltrating monocytes program resident microglia to mediate angiogenesis and cerebrovascular repair after an intracerebral hemorrhage. In the penumbrae of human stroke brain lesions, we identified a subpopulation of microglia that express vascular endothelial growth factor A. These cells, termed ‘repair-associated microglia’ (RAMs), were also observed in a rodent model of CVI and coexpressed interleukin (IL)-6Ra. Cerebrovascular repair did not occur in IL-6 knockouts or in mice lacking microglial IL-6Ra expression and single-cell transcriptomic analyses revealed faulty RAM programming in the absence of IL-6 signaling. Infiltrating CCR2+ monocytes were the primary source of IL-6 after a CVI and were required to endow microglia with proliferative and proangiogenic properties. Faulty RAM programming in the absence of IL-6 or inflammatory monocytes resulted in poor cerebrovascular repair, neuronal destruction and sustained neurological deficits that were all restored via exogenous IL-6 administration. These data provide a molecular and cellular basis for how monocytes instruct microglia to repair damaged brain vasculature and promote functional recovery after injury.

DOI: 10.1038/s41590-023-01521-1

Source: https://www.nature.com/articles/s41590-023-01521-1