Role for microglia in sex differences after ischemic stroke: importance of M2.
Role for microglia in sex differences after ischemic stroke: importance of M2.
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DOI：
10.1007/s11011-015-9714-9
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发表时间：
2015-12
影响因子：
3.6
通讯作者：
Offner H
中科院分区：
文献类型：
--
作者：
Bodhankar S;Lapato A;Chen Y;Vandenbark AA;Saugstad JA;Offner H
炎症在缺血性卒中的发病机制中起关键作用。这一过程部分依赖于由激活的驻留中枢神经系统（CNS）小胶质细胞（MG）释放的促炎因子。先前的研究表明，当在由60分钟大脑中动脉闭塞（MCAO）诱导的实验性中风之前24小时或治疗性地在4小时或之后24小时给予IL-10+ B细胞时，IL-10+ B细胞的转移减少了雄性C57 BL/6 J受体小鼠中的梗死体积。本研究评估了IL-10+ B细胞对从幼稚和缺血性卒中诱导小鼠培养的原代雄性与雌性MG的免疫调节的可能性别差异。因此，在脂多糖（LPS）活化后，用重组（r）IL-10、rIL-4或IL-10+ B细胞处理MG培养物，并通过流式细胞术评估促炎因子和抗炎因子的产生。我们发现，IL-10+ B细胞通过细胞-细胞相互作用显著降低了MCAO后MG产生的TNF-α、IL-1β和CCL 3，并增加了其抗炎M2标记物CD 206的表达。此外，与雄性小鼠相比，来自雌性小鼠的MG具有更高的IL-4和IL-10受体表达，并且增加了IL-4的产生，特别是在用IL-10+ B细胞处理后。这些发现表明，IL-10产生的B细胞在调节MG激活，促炎细胞因子释放和M2表型诱导，MCAO后，女性MG对IL-4和IL-10的敏感性增加中起着至关重要的作用。这项研究，加上我们以前的证明，增加数量的转移IL-10+ B细胞在缺血半球，提供了一个机制的基础上，局部调节分泌的IL-10和IL-4，以及直接B细胞/MG相互作用，促进M2+-MG。
Inflammation plays a critical role in the pathogenesis of ischemic stroke. This process depends, in part, upon proinflammatory factors released by activated resident central nervous system (CNS) microglia (MG). Previous studies demonstrated that transfer of IL-10+ B-cells reduced infarct volumes in male C57BL/6J recipient mice when given 24 h prior to or therapeutically at 4 h or 24 h after experimental stroke induced by 60 min middle cerebral artery occlusion (MCAO). The present study assesses possible sex differences in immunoregulation by IL-10+ B-cells on primary male vs. female MG cultured from naïve and ischemic stroke-induced mice. Thus, MG cultures were treated with recombinant (r)IL-10, rIL-4 or IL-10+ B-cells after lipopolysaccharide (LPS) activation and evaluated by flow cytometry for production of proinflammatory and anti-inflammatory factors. We found that IL-10+ B-cells significantly reduced MG production of TNF-α, IL-1β and CCL3 post-MCAO and increased their expression of the anti-inflammatory M2 marker, CD206, by cell-cell interactions. Moreover, MG from female vs. male mice had higher expression of IL-4 and IL-10 receptors and increased production of IL-4, especially after treatment with IL-10+ B-cells. These findings indicate that IL-10-producing B-cells play a crucial role in regulating MG activation, proinflammatory cytokine release and M2 phenotype induction, post-MCAO, with heightened sensitivity of female MG to IL-4 and IL-10. This study, coupled with our previous demonstration of increased numbers of transferred IL-10+ B-cells in the ischemic hemisphere, provide a mechanistic basis for local regulation by secreted IL-10 and IL-4 as well as direct B-cell/MG interactions that promote M2+-MG.