Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15213, USA.
Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
J Neuroinflammation. 2022 Oct 5;19(1):246. doi: 10.1186/s12974-022-02608-6.
Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia-OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na/H exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-Cre control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-Cre;Nhe1, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage and accelerated chronic phase of OL regeneration at 30 days post-TBI. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes in cKO mice were recapitulated in C57BL6J wild-type TBI mice receiving treatment of a potent NHE1 inhibitor HOE642 for 1-7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation in oligodendrogenesis and neuroprotection, which contributes to accelerated brain repair and neurological function recovery after TBI.
小胶质细胞的炎症反应差异在调节脑白质少突胶质细胞（OL）的分化和成熟中起作用。创伤性脑损伤（TBI）如何改变小胶质细胞-OL 串扰及其对轴突髓鞘形成和神经功能损伤的影响仍知之甚少。在这项研究中，我们研究了 Na/H 交换器（NHE1）在小胶质细胞原代炎症激活和 OL 存活和分化中的作用，NHE1 是一种必需的小胶质细胞 pH 调节蛋白，该研究采用控制皮质撞击诱导的小鼠 TBI 模型。在 Cx3cr1-Cre 对照（Ctrl）小鼠和选择性小胶质细胞 Nhe1 敲除（Cx3cr1-Cre；Nhe1，Nhe1 cKO）小鼠中检测到类似的 TBI 诱导挫伤体积。与 Ctrl 小鼠相比，Nhe1 cKO 小鼠对初始 TBI 诱导的白质损伤具有更高的抵抗力，并在 TBI 后 30 天加速了 OL 再生的慢性期。cKO 大脑显示出小胶质细胞和浸润的髓样细胞的抗炎表型增加，促炎转录组谱减少。此外，cKO 小鼠在 TBI 后表现出更快的感觉运动和认知功能恢复。在接受强效 NHE1 抑制剂 HOE642 治疗的 C57BL6J 野生型 TBI 小鼠中，cKO 小鼠的这些表型结果可再现，治疗时间为 TBI 后 1-7 天。综上所述，这些发现共同表明，阻断 NHE1 蛋白刺激 OL 发生和神经保护中的修复性小胶质细胞激活，有助于 TBI 后加速大脑修复和神经功能恢复。
