<scp>ProS</scp> /Mer Alleviates Sepsis‐Induced Neuromuscular Dysfunction by Inhibiting <scp>TLR4</scp> / <scp>MyD88</scp> / <scp>NF</scp> ‐ <scp>κB</scp> Signals

ABSTRACT Sepsis frequently leads to profound neuromuscular dysfunction, in part driven by spinal neuroinflammation. The receptor tyrosine kinase Mer is a key regulator of immune homeostasis, yet its role in sepsis‐induced neuromuscular impairment remains unclear. This study investigated the contribution of Mer signaling to spinal neuroinflammation and neuromuscular dysfunction in sepsis. Sepsis was induced in rats using the cecal ligation and puncture (CLP) model. Neuromuscular function was assessed by muscle mass analysis, compound muscle action potential (CMAP) recordings, and nerve conduction studies. Neuronal survival and neuromuscular junction (NMJ) integrity were evaluated histologically. Spinal inflammatory responses and signaling pathways were analyzed by measuring cytokine levels, microglial activation, and expression of TLR4/MyD88/NF‐κB and STAT1/SOCS pathway components. To assess therapeutic potential, the Mer ligand Protein S (ProS) was administered intrathecally in both wild‐type (WT) and Mer‐deficient (Mer ‐/‐ ) rats. Mer deficiency significantly aggravated sepsis‐induced muscle wasting, reduced CMAP amplitude, prolonged latency, impaired motor conduction velocity, increased neuronal loss, and exacerbated NMJ disintegration. These functional impairments were associated with elevated spinal IL‐6 and TNF‐α levels, enhanced microglia/macrophage activation, upregulated TLR4/MyD88/NF‐κB signaling, and suppressed STAT1/SOCS pathway activation. Intrathecal ProS treatment markedly improved neuromuscular performance, attenuated spinal inflammatory responses, and restored neuronal integrity and NMJ structure in both WT and Mer ‐/‐ CLP rats. ProS/Mer signaling plays a critical protective role in sepsis‐induced neuromuscular dysfunction by suppressing pro‐inflammatory pathways and activating anti‐inflammatory STAT1/SOCS signaling in the spinal cord. Therapeutic targeting of the ProS/Mer axis may represent a promising strategy for the treatment of sepsis‐associated neuromyopathy.