RPSA-OLFM4 axis governs neutrophil migration against bacterial infection and sepsis.

Summary

Using myeloid-specific knockout mice, patient neutrophils, and in vivo therapeutic modulation, this study identifies an RPSA-OLFM4 checkpoint that enables neutrophil migration by sustaining RhoA/ROCK1/pMLC2 signaling and MYH9 localization. Targeting this axis restored migration and improved outcomes in infected and septic mice, positioning it as a tractable host-defense strategy.

Key Findings

• Myeloid-specific Rpsa deletion reduced neutrophil infiltration and worsened Streptococcus suis serotype 2 infection.
• RPSA deficiency upregulated OLFM4, inhibited RhoA/ROCK1/pMLC2 signaling, reduced MYH9, and mislocalized MYH9 from uropods, disrupting migration.
• Neutrophils from septic patients showed decreased RPSA and increased OLFM4 associated with impaired migratory capacity.
• Therapeutic targeting of the RPSA-OLFM4 axis restored neutrophil migration and improved outcomes in infected and septic mice.

Clinical Implications

Although preclinical, modulating the RPSA-OLFM4 axis could augment neutrophil trafficking and bacterial clearance in sepsis; patient biomarker development (RPSA/OLFM4) may enable risk stratification for impaired neutrophil migration.

Limitations

• Preclinical models centered on S. suis may limit pathogen generalizability
• Human data are observational without interventional validation
• Potential species-specific differences in neutrophil regulation

Future Directions

Test RPSA-OLFM4 modulation across diverse pathogens, develop clinical-grade assays for RPSA/OLFM4, and evaluate safety/efficacy in early-phase sepsis trials.