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BAY61‑3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury

  • Authors:
    • Xuejun He
    • Yimin Huang
    • Yanchao Liu
    • Xincheng Zhang
    • Pengjie Yue
    • Xiaopeng Ma
    • Zhuangzhuang Miao
    • Xiaobing Long
    • Yiping Yang
    • Xueyan Wan
    • Jin Lei
    • Kai Shu
    • Ting Lei
    • Chao Gan
    • Huaqiu Zhang

  • View Affiliations

  • Published online on: November 9, 2021     https://doi.org/10.3892/ijmm.2021.5060
  • Article Number: 5

  • Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Neuroinflammatory processes mediated by microglial activation and subsequent neuronal damage are the hallmarks of traumatic brain injury (TBI). As an inhibitor of the macrophage‑inducible C‑type lectin (Mincle)/spleen tyrosine kinase (Syk) signaling pathway, BAY61‑3606 (BAY) has previously demonstrated anti‑inflammatory 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 µM) in vitro. The levels of inflammatory factors in microglia were assessed using reverse transcription‑quantitative 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/NF‑κB signaling pathway [Mincle, phosphorylated (p)‑Syk and NF‑κB], in addition to proteins associated with inflammation (ASC, caspase‑1, TNF‑α, IL‑1β and IL‑6), apoptosis (Bax and Bim) and tight junctions (Claudin‑5), 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/NF‑κB signaling pathway (including Mincle, p‑Syk and p‑NF‑κB), inflammatory cytokines (TNF‑α, IL‑1β and IL‑6), proteins involved in inflammation (ASC and caspase‑1), apoptotic markers (Bax and Bim) and the tight junction protein Claudin‑5 were significantly altered post‑TBI. BAY treatment reversed these effects in both the cerebral cortex extract‑induced 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 TBI‑induced neurovascular unit damage and neurological function deficits. Taken together, these findings provided evidence that BAY may inhibit the Mincle/Syk/NF‑κB signaling pathway in microglia; this in turn could attenuate microglia‑mediated neuroinflammation and improve neurological deficits following TBI.
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January-2022
Volume 49 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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  • CiteScore: 10.7
  • CiteScore Rank: Q1: #35/328 Biochemistry, Genetics and Molecular Biology
  • Source Normalized Impact per Paper (SNIP): 0.994
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Spandidos Publications style
He X, Huang Y, Liu Y, Zhang X, Yue P, Ma X, Miao Z, Long X, Yang Y, Wan X, Wan X, et al: BAY61‑3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury. Int J Mol Med 49: 5, 2022
APA
He, X., Huang, Y., Liu, Y., Zhang, X., Yue, P., Ma, X. ... Zhang, H. (2022). BAY61‑3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury. International Journal of Molecular Medicine, 49, 5. https://doi.org/10.3892/ijmm.2021.5060
MLA
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."BAY61‑3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury". International Journal of Molecular Medicine 49.1 (2022): 5.
Chicago
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."BAY61‑3606 attenuates neuroinflammation and neurofunctional damage by inhibiting microglial Mincle/Syk signaling response after traumatic brain injury". International Journal of Molecular Medicine 49, no. 1 (2022): 5. https://doi.org/10.3892/ijmm.2021.5060