Neuroinflammation and Gene Therapy Lab., Institut Pasteur de Montevideo, Montevideo, Uruguay.
Departamento de Histología y Embriología, Facultad de Medicina, UdelaR, Montevideo, Uruguay.
Sci Rep. 2023 Oct 5;13(1):16796. doi: 10.1038/s41598-023-43840-1.
Emerging evidences suggest that immune receptors participate in diverse microglial and macrophage functions by regulating their immunometabolism, inflammatory phenotype and phagocytosis. CD300f, a TREM2-like lipid sensing immune receptor, that integrates activating and inhibitory cell-signalling pathways, modulates inflammation, efferocytosis and microglial metabolic fitness. In particular, CD300f overexpression was described to be neuroprotective after an acute brain injury, suggesting a role for this immune receptor in neurotrophic interactions. Thus, we hypothesised that CD300f modulates neuronal survival through neuron-microglial interactions. In order to study its biological function, we used in vitro and in vivo approaches, CD300f animals and rCD300f-Fc, a fusion protein that interrupts the endogen interaction between CD300f receptor-ligands. In hippocampal cocultures containing neurons and mixed glia, we observed that rCD300f-Fc, but not control IgGs induced neuronal death. In accordance, in vivo studies performed by injecting rCD300f-Fc or control IgGs into rat or WT or CD300 KO mice neocortex, showed an increased lesioned area after a penetrating brain injury. Interestingly, this neuronal death was dependent on glia, and the neurotoxic mechanism did not involve the increase of proinflammatory cytokines, the participation of NMDA receptors or ATP release. However, exogenous addition of glial cell line-derived neurotrophic factor (GDNF) prevented this process. Taken together, our results suggest that CD300f modulates neuronal survival in vitro and after a penetrating brain injury in vivo and that CD300f inhibition alters microglial phenotype generating a neurotoxic microenvironment.
新出现的证据表明，免疫受体通过调节其免疫代谢、炎症表型和吞噬作用，参与多种小胶质细胞和巨噬细胞的功能。CD300f 是一种类似 Trem2 的脂质感应免疫受体，它整合了激活和抑制细胞信号通路，调节炎症、吞噬作用和小胶质细胞代谢适应性。特别是，CD300f 的过表达被描述为急性脑损伤后的神经保护作用，这表明该免疫受体在神经营养相互作用中具有作用。因此，我们假设 CD300f 通过神经元-小胶质细胞相互作用调节神经元的存活。为了研究其生物学功能，我们使用了体外和体内方法、CD300f 动物和 rCD300f-Fc（一种中断 CD300f 受体-配体内源性相互作用的融合蛋白）。在含有神经元和混合神经胶质的海马共培养物中，我们观察到 rCD300f-Fc，但不是对照 IgG，诱导神经元死亡。与此一致，在向大鼠或 WT 或 CD300 KO 小鼠新皮质内注射 rCD300f-Fc 或对照 IgG 的体内研究中，在穿透性脑损伤后显示出损伤区域增加。有趣的是，这种神经元死亡依赖于神经胶质，并且神经毒性机制不涉及促炎细胞因子的增加、NMDA 受体的参与或 ATP 的释放。然而，外源性添加胶质细胞系衍生的神经营养因子 (GDNF) 可防止这一过程。总之，我们的结果表明，CD300f 调节体外神经元存活和体内穿透性脑损伤后的神经元存活，CD300f 抑制改变小胶质细胞表型，产生神经毒性微环境。
