ProS/Mer Alleviates Sepsis-Induced Neuromuscular Dysfunction by Inhibiting TLR4/MyD88/NF-κB Signals

Area of Science:

• Neuroscience
• Immunology
• Sepsis Research

Background:

• Sepsis often causes neuromuscular dysfunction, partly due to spinal neuroinflammation.
• The role of Mer signaling in sepsis-induced neuromuscular impairment is not well understood.

Purpose of the Study:

• To investigate the role of Mer signaling in spinal neuroinflammation and neuromuscular dysfunction during sepsis.
• To evaluate the therapeutic potential of Protein S (ProS) in a rat model of sepsis.

Main Methods:

• Sepsis induced via cecal ligation and puncture (CLP) in rats.
• Neuromuscular function assessed via muscle mass, compound muscle action potentials (CMAP), and nerve conduction.
• Spinal inflammation, neuronal survival, and neuromuscular junction (NMJ) integrity analyzed.
• Intrathecal ProS administered to wild-type and Mer-deficient rats.

Main Results:

• Mer deficiency exacerbated sepsis-induced muscle wasting, reduced CMAP, and impaired nerve conduction.
• Impairments correlated with increased spinal IL-6/TNF-α, microglial activation, and TLR4/MyD88/NF-κB signaling.
• ProS treatment improved neuromuscular function and attenuated spinal inflammation in both genotypes.
• ProS treatment restored neuronal integrity and NMJ structure.

Conclusions:

• ProS/Mer signaling is crucial for protecting against sepsis-induced neuromuscular dysfunction.
• This pathway suppresses spinal pro-inflammatory responses and activates anti-inflammatory STAT1/SOCS signaling.
• Targeting the ProS/Mer axis offers a potential therapeutic strategy for sepsis-associated neuromyopathy.