小胶质细胞
创伤性脑损伤
白质
促炎细胞因子
条件基因敲除
神经科学
少突胶质细胞
CX3CR1型
生物
炎症
表型
医学
中枢神经系统
免疫学
髓鞘
磁共振成像
趋化因子
生物化学
趋化因子受体
放射科
精神科
基因
作者
Shanshan Song,Md Nabiul Hasan,Lauren Yu,Satya S. Paruchuri,John P. Bielanin,Shamseldin Metwally,Sydney Fischer,Victoria M. Fiesler,Tanusree Sen,Rajaneesh Gupta,Lesley M. Foley,T. Kevin Hitchens,C. Edward Dixon,Franca Cambi,Nilkantha Sen,Dandan Sun
出处
期刊:Research Square - Research Square
日期:2022-06-28
标识
DOI:10.21203/rs.3.rs-1790060/v1
摘要
Abstract 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 ERT2 control (Ctrl) mice and selective microglial Nhe1 knockout ( Cx3cr1-Cre ERT2 ;Nhe1 flox/flox , 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 d 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 received 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 and oligodendrogenesis, which contributes to accelerated white matter repair and neurological function recovery after TBI.
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