Soluble Trem2 is a negative regulator of erythrophagocytosis after intracerebral hemorrhage in a CD36 receptor recycling manner.
Soluble Trem2 is a negative regulator of erythrophagocytosis after intracerebral hemorrhage in a CD36 receptor recycling manner.
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可溶性Trem2是脑出血后以CD36受体循环方式吞噬红细胞的负调节因子
DOI：
10.1016/j.jare.2022.03.011
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发表时间：
2023-02
影响因子：
10.7
通讯作者：
Chen, Gao
中科院分区：
文献类型：
--
作者：
Zhou, Hang;Li, Jianru;Hu, Libin;Yu, Jiahui;Fu, Xiongjie;Liang, Feng;Yan, Feng;Chen, Gao
sTrem 2通过抑制Vps 35介导的促红细胞吞噬分子受体CD 36再循环和未再循环的CD 36的溶酶体降解，重塑ICH相关的小胶质细胞/巨噬细胞，损害红细胞吞噬作用并增强炎症，导致ICH后神经元丢失和神经功能障碍的加重。可溶性Trem 2延迟ICH后小胶质细胞/巨噬细胞介导的血肿消退可溶性Trem 2在全长Trem 2非依赖性途径中调节红细胞吞噬作用可溶性Trem 2抑制CD 36受体再循环并加剧小胶质细胞/巨噬细胞中未再循环的CD 36的溶酶体降解。小胶质细胞和巨噬细胞参与脑出血（ICH）后的血肿清除，从而促进组织修复和神经功能恢复。在髓样细胞2（Trem 2）上表达的触发受体已被指示为小胶质细胞/巨噬细胞表面上的主要病理诱导的免疫信号传导枢纽。可溶性Trem 2（sTrem 2）是Trem 2的蛋白水解形式，其在体液中丰富并且与病理过程正相关。在本研究中，我们的目的是研究sTrem 2在ICH后血肿消退中的潜在作用，并阐明其潜在机制。我们通过立体定位注射重组sTrem 2蛋白或通过腺相关病毒介导的表达来探索sTrem 2在小鼠ICH脑中的生物学功能。采用流式细胞术和免疫荧光法评估红细胞吞噬作用。进行蛋白质印迹以评估蛋白质表达。检查行为、sTrem 2诱导的下游通路和小胶质细胞的变化。sTrem 2阻碍血肿消退并损害功能性运动和感觉恢复。有趣的是，sTrem 2绕过全长Trem 2，负调节小胶质细胞/巨噬细胞噬红细胞作用，并促进炎性表型，这与减少的逆转录酶水平和受损的促噬红细胞受体CD 36的再循环有关。逆转录酶Vps 35的拯救消除了sTrem 2引起的吞噬抑制作用和溶酶体依赖性CD 36降解。这些研究结果表明，sTrem 2作为一个负性因子，对小胶质细胞/巨噬细胞介导的血肿和相关的神经元损伤清除，提供了深入了解红细胞吞噬作用的调节机制，以及如何可能在ICH后受损，并表明，抗蛋白水解活性的Trem 2可以探索ICH治疗。
sTrem2 reshapes the ICH-associated microglia/macrophages impairing erythrophagocytosis and enhancing inflammation via inhibition of Vps35-mediated pro-erythrophagocytic molecular receptor CD36 recycling and lysosomal degradation of unrecycled CD36, causing exacerbation of neuronal loss and neurological dysfunction after ICH. Soluble Trem2 delays the microglia/macrophages mediated hematoma resolution after ICH Soluble Trem2 modulates erythrophagocytosis in a full-length Trem2 independent pathway. Soluble Trem2 inhibits CD36 receptor recycling and exacerbates lysosomal degradation of unrecycled CD36 in microglia/macrophages. Microglia and macrophages participate in hematoma clearance after intracerebral hemorrhage (ICH), thereby facilitating tissue restoration and neurological recovery. Triggering receptor expressed on myeloid cells 2 (Trem2) has been indicated as a major pathology-induced immune signaling hub on the microglial/macrophage surface. Soluble Trem2 (sTrem2), the proteolytic form of Trem2, is abundant in the body fluid and is positively correlated with the pathological process. In the present study, we aimed to investigate the potential role of sTrem2 in hematoma resolution after ICH and to elucidate its underlying mechanisms. We explored the biological functions of sTrem2 in the murine ICH brain by stereotaxic injection of recombinant sTrem2 protein or by adeno-associated virus-mediated expression. Erythrocyte phagocytosis was assessed using flow cytometry and immunofluorescence. Western blotting was performed to evaluate protein expression. Changes in behavior, sTrem2-induced down-stream pathway, and microglia were examined. sTrem2 impedes hematoma resolution and impairs functional motor and sensory recovery. Interestingly, sTrem2 bypasses full-length Trem2, negatively regulating microglial/macrophage erythrophagocytosis, and promotes an inflammatory phenotype, which is associated with reduced retromer levels and impaired recycling of the pro-erythrophagocytic receptor CD36. Rescue of retromer Vps35 abolishes the phagocytosis-inhibiting effects and lysosome-dependent CD36 degradation caused by sTrem2. These findings indicate sTrem2 as a negative factor against microglia/macrophage-mediated hematoma and related neuronal damage clearance, provide insight into the mechanisms by which erythrophagocytosis is regulated and how it may be impaired after ICH, and suggest that the anti-proteolytic activity of Trem2 can be explored for ICH therapy.
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影响因子：
9.3
作者：
Fassler M;Rappaport MS;Cuño CB;George J
通讯作者：
George J
影响因子：
168.9
作者：
Hanley, Daniel F.;Thompson, Richard E.;Awad, Issam A.
通讯作者：
Awad, Issam A.
影响因子：
2
作者：
Kwon, Hyuk Sung;Lee, Eun-Hye;Koh, Seong-Ho
通讯作者：
Koh, Seong-Ho
影响因子：
4.6
作者：
Kim SM;Mun BR;Lee SJ;Joh Y;Lee HY;Ji KY;Choi HR;Lee EH;Kim EM;Jang JH;Song HW;Mook-Jung I;Choi WS;Kang HS
通讯作者：
Kang HS
DOI：
10.1038/jcbfm.2008.114
发表时间：
2009-01
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
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作者：
通讯作者：
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