ProS/Mer alleviates sepsis-induced neuromuscular dysfunction by inhibiting TLR4/MyD88/NF-κB signals

Abstract

Background Sepsis remains a significant cause of morbidity and mortality worldwide, with systemic inflammation and behavioral impairment. Microglia are well-known critical regulators of neuroinflammation, which feature in multiple neurodegenerative disorders. These cells become “activated” through stimulation of toll-like receptors (TLRs), resulting in changes in morphology and production and release of cytokines. Myeloid-epithelial-reproductive tyrosine kinase (Mer), a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, regulates multiple features of microglial/macrophage physiology. The present study examined the roles of the related TAM receptors, Mer, and its ligand, Protein S (ProS), in regulating neuroinflammation and neuromuscular function following sepsis. Methods The sepsis was established by cecal ligation and puncture (CLP) in wildtype (WT) and Mer−/− rats, and recombinant protein S (ProS) or normal saline (NS) was intrathecally injected for intervention. The muscle weight, neuromuscular function, Nissl staining, immunofluorescence, ELISA, and Western blot were performed. Results Knockout of Mer showed significantly decreased muscle weight and neuromuscular function at day 4 post-CLP, as well as increased inflammatory cytokines, activated microglia/macrophage, and TLR4/MyD88/NF-κB signal pathway in the spinal cord. The administration of ProS activated the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway and inhibited the TLR4/MyD88/NF-κB signal pathway, which alleviated the neuromuscular dysfunction after CLP. Conclusion ProS/Mer alleviates muscle atrophy and neuromuscular dysfunction in the sepsis model by activating the STAT1/SOCS signaling pathway and inhibiting the TLR4/MyD88/NF-κB signaling pathway.