Sepsis Activats the TLR4/MYD88 Pathway in Schwann Cells to Promote Infiltration of Macrophages, Thereby Impeding Neuromuscular Function.

INTRODUCTION: Sepsis is a kind of maladjustment response to bacterial infection and activation of coagulation, which can induce neuromuscular dysfunction. However, there is scarce of experimental evidence about the relationship between Schwann cells (SCs) and sepsis in neuromuscular dysfunction. We therefore set out to identify the potential role of SCs in sepsis-induced neuromuscular dysfunction and to explore the underlying molecular mechanism. METHODS: Primary SCs were isolated from the left hind limb sciatic nerve of sepsis mice, which was constructed by cecal ligation and puncture. Then, the SCs were infected with adenovirus encoding TLR4, MyD88, or IL-1R (with lipopolysaccharide stimulation), and the Raw 264.7 macrophages were injected with adenovirus with CCR2 silencing (with mMCP-1 stimulation). Further investigation of the IL-1β and MCP-1 expressions, we followed RT-qPCR and ELISA techniques, the F4/80 and Ki67 expressions was observed by immunofluorescence staining, while the expressions of CCR2, FAK/p-FAK, NFκB/p-NFκB, and ERK1/2/p-ERK1/2 was determined by Western blot analysis. Least but last, the cell migration ability and cell proliferation ability were detected by Transwell assay and Flow cytometry respectively. RESULTS: Our results showed that in sepsis mice, the TLR4/MyD88/ERK pathway was activated in SCs, which triggered the cells to secrete IL-1β and MCP-1. The secreted IL-1β bound with IL-1β receptor on the surface of SCs, thereby activating the IL-1β/IL-1R/MyD88/ERK pathway and further promoting the secretion of MCP-1 by SCs. MCP-1 was found to bind to CCR2 on the surface of Raw264.7 macrophages to activate the TLR4/MyD88/ERK pathway which caused the inhibition of neuromuscular function. CONCLUSION: Sepsis significantly promotes the infiltration of macrophages by activating the TLR4/MyD88 pathway in SCs, thereby impeding neuromuscular function. Consistently, our study provides a novel concept in the area of neuromuscular dysfunction therapeutics following sepsis.