BAY61‑3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury.
He X, Huang Y, Liu Y, Zhang X, Yue P, Ma X, Miao Z, Long X, Yang Y, Wan X, Lei J, Shu K, Lei T, Gan C, Zhang H.
International journal of molecular medicine. 2022; 49(1):

Abstract

Neuroinflammatory processes mediated by microglial activation and subsequent neuronal damage are the hallmarks of traumatic brain injury (TBI). As an inhibitor of the macrophageinducible Ctype lectin (Mincle)/spleen tyrosine kinase (Syk) signaling pathway, BAY613606 (BAY) has previously demonstrated antiinflammatory effects on some pathological processes, such as acute kidney injury, by suppressing the inflammatory macrophage response. In the present study, the potential effects of BAY on microglial phenotype and neuroinflammation after TBI were investigated. BAY (3 mg/kg) was first administered into mice by intraperitoneal injection after TBI induction in vivo and microglia were also treated with BAY (2 microM) in vitro. The levels of inflammatory factors in microglia were assessed using reverse transcriptionquantitative PCR and ELISA. Cortical neuron, myelin sheath, astrocyte and cerebrovascular endothelial cell markers were detected using immunofluorescence. The levels of components of the Mincle/Syk/NFkappaB signaling pathway [Mincle, phosphorylated (p)Syk and NFkappaB], in addition to proteins associated with inflammation (ASC, caspase1, TNFalpha, IL1beta and IL6), apoptosis (Bax and Bim) and tight junctions (Claudin5), were measured via western blotting and ELISA. Migration and chemotaxis of microglial cells were evaluated using Transwell and agarose spot assays. Neurological functions of the mice were determined in vivo using the modified neurological severity scoring system and a Morris water maze. The results of the present study revealed that the expression levels of proteins in the Mincle/Syk/NFkappaB signaling pathway (including Mincle, pSyk and pNFkappaB), inflammatory cytokines (TNFalpha, IL1beta and IL6), proteins involved in inflammation (ASC and caspase1), apoptotic markers (Bax and Bim) and the tight junction protein Claudin5 were significantly altered postTBI. BAY treatment reversed these effects in both the cerebral cortex extractinduced cell model and the controlled cortical impact mouse model. BAY was also revealed to suppress activation of the microglial proinflammatory phenotype and microglial migration. In addition, BAY effectively attenuated TBIinduced neurovascular unit damage and neurological function deficits. Taken together, these findings provided evidence that BAY may inhibit the Mincle/Syk/NFkappaB signaling pathway in microglia; this in turn could attenuate microgliamediated neuroinflammation and improve neurological deficits following TBI.



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