CD300a blockade enhances efferocytosis by infiltrating myeloid cells and ameliorates neuronal deficit after ischemic stroke
CD300a blockade enhances efferocytosis by infiltrating myeloid cells and ameliorates neuronal deficit after ischemic stroke
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DOI：
10.1126/sciimmunol.abe7915
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发表时间：
2021-10-01
影响因子：
24.8
通讯作者：
Shibuya, Akira
中科院分区：
文献类型：
--
作者：
Nakahashi-Oda, Chigusa;Fujiyama, Satoshi;Shibuya, Akira
免疫反应有助于缺血性中风期间和之后的组织损伤和修复。然而，时空和起始分子事件仍不完全清楚。在这里，我们发现，缺乏磷脂酰丝氨酸受体 CD300a 的小鼠在大脑中动脉闭塞 (MCAO) 后表现出改善的神经功能缺损，该受体在包括 Ly6Chi 单核细胞在内的脑髓细胞中高度表达。 CD300a 通过 CD300b-DNAX 激活蛋白 12 (DAP12) 信号通路抑制信号传导，以防止凋亡细胞的胞吞作用。 CD300a 的缺乏会增强 MCAO 后 1 小时内骨髓细胞浸润大脑的胞吞作用，并减少死细胞释放损伤相关分子模式，导致半暗区炎症较轻。抗 CD300a 中和抗体治疗可改善 MCAO 后的神经功能缺损。这些发现揭示了胞吞作用在缺血性中风病理学超急性期中的重要作用，并确定 CD300a 作为治疗缺血性中风的免疫疗法的靶点。
Immune responses contribute to tissue injury and repair during and after ischemic stroke. However, the spatiotemporal and initiating molecular events remain incompletely understood. Here, we show that mice deficient in the phosphatidylserine receptor CD300a, which is highly expressed on brain myeloid cells including Ly6Chi monocytes, exhibited ameliorated neurological deficit after middle cerebral artery occlusion (MCAO). CD300a inhibited signaling through the CD300b-DNAX-activation protein 12 (DAP12) signaling pathway to prevent efferocytosis of apoptotic cells. Deficiency of CD300a enhanced efferocytosis by myeloid cells infiltrating the brain as early as 1 hour after MCAO and reduced release of damage-associated molecular patterns from dead cells, resulting in milder inflammation in the penumbral region. Treatment with an anti-CD300a neutralizing antibody ameliorated the neurological deficit after MCAO. These findings reveal an important role of efferocytosis in the super-acute phase of ischemic stroke pathology and identified CD300a as a target for immunotherapy in treating ischemic stroke.