Journal of Advanced Research ( IF 11.4 ) Pub Date : 2022-03-18 , DOI: 10.1016/j.jare.2022.03.011 Hang Zhou 1 , Jianru Li 1 , Libin Hu 1 , Jiahui Yu 1 , Xiongjie Fu 1 , Feng Liang 1 , Feng Yan 1 , Gao Chen 1
|
Introduction
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.
Objectives
In the present study, we aimed to investigate the potential role of sTrem2 in hematoma resolution after ICH and to elucidate its underlying mechanisms.
Methods
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.
Results
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.
Conclusion
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.
中文翻译：
可溶性 Trem2 是脑出血后红细胞吞噬作用的负调节因子，以 CD36 受体循环方式
介绍
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。在骨髓细胞 2 (Trem2) 上表达的触发受体已被证明是小胶质细胞/巨噬细胞表面的主要病理诱导免疫信号中枢。可溶性 Trem2 (sTrem2) 是 Trem2 的蛋白水解形式，在体液中含量丰富，与病理过程呈正相关。
目标
在本研究中，我们旨在研究 sTrem2 在 ICH 后血肿消退中的潜在作用，并阐明其潜在机制。
方法
我们通过立体定向注射重组 sTrem2 蛋白或通过腺相关病毒介导的表达，探索了 sTrem2 在小鼠 ICH 大脑中的生物学功能。使用流式细胞术和免疫荧光评估红细胞吞噬作用。进行蛋白质印迹以评估蛋白质表达。检查了行为、sTrem2 诱导的下游通路和小胶质细胞的变化。
结果
sTrem2 阻碍血肿消退并损害功能性运动和感觉恢复。有趣的是，sTrem2 绕过全长 Trem2，负向调节小胶质细胞/巨噬细胞红细胞吞噬作用，并促进炎症表型，这与逆转录酶水平降低和促红细胞吞噬细胞受体 CD36 的循环受损有关。挽救逆转录酶 Vps35 消除了由 sTrem2 引起的吞噬作用抑制作用和溶酶体依赖性 CD36 降解。
结论
这些发现表明 sTrem2 是对抗小胶质细胞/巨噬细胞介导的血肿和相关神经元损伤清除的负面因素，提供了对调节红细胞吞噬作用的机制及其在 ICH 后如何受损的见解，并表明 Trem2 的抗蛋白水解活性可以探索用于 ICH 治疗。
京公网安备 11010802027423号