NMI Functions as Immuno-regulatory Molecule in Sepsis by Regulating Multiple Signaling Pathways

Area of Science:

• Immunology and Inflammation Research
• Molecular Biology and Signaling Pathways
• Sepsis Pathophysiology

Background:

• Sepsis causes organ damage via overactive inflammation, immune, and coagulation dysfunction.
• Danger-associated molecular pattern (DAMP) molecules are key drivers of sepsis-induced inflammation.
• Previous work identified NMI as a DAMP molecule promoting sepsis inflammation via TLR4/NF-κB.

Purpose of the Study:

• To investigate the role of NMI in sepsis beyond its known TLR4/NF-κB interaction.
• To identify additional receptors and signaling pathways influenced by NMI in sepsis.
• To elucidate the comprehensive functional mechanism of NMI in sepsis pathogenesis.

Main Methods:

• Analysis of bulk and single-cell transcriptome data from the GEO database for NMI expression.
• Bioinformatic analysis to correlate NMI expression with key inflammatory signaling pathways (NF-κB, MAPK, JAK).
• Experimental validation using RAW cells to assess STAT1 phosphorylation upon NMI stimulation.

Main Results:

• NMI expression is significantly increased in neutrophils and monocytes of sepsis patients.
• NMI likely interacts with multiple receptors including IFNAR1, IFNAR2, TNFR1, TLR3, TLR1, IL9R, IL10RB, and TLR4.
• NMI correlates with activation of NF-κB, MAPK, and JAK pathways, leading to pro-inflammatory cytokine release.
• NMI stimulation enhances STAT1 phosphorylation, confirming JAK pathway activation.

Conclusions:

• NMI plays a significant role in exacerbating sepsis-induced inflammation through multiple receptor-mediated pathways.
• NMI activates NF-κB, MAPK, and JAK signaling cascades, contributing to the pro-inflammatory state in sepsis.
• These findings reveal a broader functional mechanism of NMI in sepsis, highlighting its potential as a therapeutic target.