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

Summary

Using myeloid-specific knockout mice, human septic neutrophils, and rescue interventions, this study identifies RPSA as a suppressor of OLFM4 that maintains RhoA/ROCK1/pMLC2 signaling, MYH9 dynamics, and neutrophil polarity. Therapeutically targeting the RPSA–OLFM4 axis restored neutrophil migration and improved outcomes in septic mouse models.

Key Findings

• Myeloid-specific Rpsa deletion reduced neutrophil infiltration and worsened Streptococcus suis serotype 2 infection.
• RPSA deficiency upregulated OLFM4, suppressing RhoA/ROCK1/pMLC2 signaling, reducing MYH9, and disrupting uropod extension and polarity.
• Neutrophils from septic patients showed decreased RPSA and increased OLFM4 correlating with impaired migration.
• Therapeutic targeting of the RPSA–OLFM4 axis restored neutrophil migration and improved outcomes in infected and septic mice.

Clinical Implications

Suggests a druggable pathway to enhance neutrophil trafficking in bacterial sepsis and positions OLFM4/RPSA expression as potential biomarkers for impaired neutrophil migration.

Limitations

• Preclinical models may not fully capture human sepsis heterogeneity and comorbidities
• Human validation is correlational; therapeutic strategies were not tested in clinical trials

Future Directions

Validate RPSA/OLFM4 as biomarkers in prospective sepsis cohorts; develop and test small molecules or biologics modulating the axis; assess safety/efficacy in early-phase trials.