Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis.

Summary

This mechanistic study shows that an ADAP–BTK–mTOR–STAT3 signaling axis drives TLR4-induced PDPN upregulation, generating an M2-like PDPNhi macrophage subset with enhanced phagocytosis that protects against sepsis. Pharmacologic STAT3 activation expanded PDPNhi macrophages and reduced sepsis severity in mice.

Key Findings

• ADAP-deficient macrophages failed to upregulate PDPN after TLR4 stimulation; reconstitution of ADAP rescued PDPN induction.
• A PDPNhi peritoneal macrophage subset with M2-like phenotype and enhanced phagocytosis formed in WT but not in ADAP-deficient septic mice; blocking this subset worsened sepsis.
• BTK-mediated phosphorylation of ADAP (Y571) with mTOR converged on STAT3 activation to transactivate the PDPN promoter.
• STAT3 agonism expanded PDPNhi macrophages and alleviated sepsis severity in vivo.

Clinical Implications

Suggests immunomodulatory strategies (e.g., STAT3 agonists or BTK/mTOR tuning) to enhance protective PDPNhi macrophages in sepsis. Human validation is needed before translation.

Limitations

• Preclinical mouse-centric work without human validation of PDPNhi macrophages
• Potential off-target effects and safety of STAT3 agonists not addressed

Future Directions

Validate PDPNhi macrophages and ADAP–STAT3 signaling in human sepsis; test clinically tractable modulators (e.g., BTK inhibitors/agonists, STAT3 modulators) and delineate tissue-specific roles.