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J Neuroimmunol ; 359: 577688, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34390950

ABSTRACT

Excess inflammatory microglia activation deteriorates the pathological degree of spinal cord injury (SCI). We here employed microglia samples in vitro and murine model in vivo to trace the role of inhibition of Arhgef3 in inflammatory response post SCI. From the specimen analysis of lipopolysaccharide (LPS)-induced inflammatory microglia, we found that Arhgef3 expression was positively relative to microglia activation. In vitro, LPS caused the microglia inflammatory activation and induced upregulation of the Arhgef3 expression. Interestingly, presence of Arhgef3 could activate RhoA through promoting Rho GTPases, but silencing of Arhgef3 decreased RhoA activation and inhibited the microglia inflammation. Moreover, disruption of Arhgef3 inhibited the GTP-RhoA, resulted in a suppression of proinflammatory cytokines, and alleviated the LPS-elicited inflammatory genes expression. Moreover, artificially decreasing Arhgef3 expression remarkedly reduced ROS generation after LPS treatment. In vivo of a mouse mechanical contusion-induced SCI model, inhibition of Arhgef3 reduced the ratio of GTP-RhoA/Total-RhoA, and prevented SCI via mitigating the microglial inflammatory phenotype and decreased secondary neurological injury. Besides, inhibition of Arhgef3 prevented alleviated the degree of demyelination but did not affect neuronal regeneration. Meaningfully, absence of Arhgef3 improved mouse locomotor recovery post SCI. Taken together, Arhgef3 involves the microglial activation and inflammatory response following neural injury, and targeted disrupting of which may indicate a promising therapeutic direction in preventing SCI.


Subject(s)
Microglia/metabolism , Rho Guanine Nucleotide Exchange Factors/antagonists & inhibitors , Rho Guanine Nucleotide Exchange Factors/biosynthesis , Spinal Cord Injuries/metabolism , rhoA GTP-Binding Protein/antagonists & inhibitors , rhoA GTP-Binding Protein/metabolism , Animals , Gene Expression , Gene Knockdown Techniques/methods , Locomotion/physiology , Male , Mice , Mice, Inbred C57BL , Rho Guanine Nucleotide Exchange Factors/genetics , Spinal Cord Injuries/genetics
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