Mac-1 blockade impedes adhesion-dependent neutrophil extracellular trap formation and ameliorates lung injury in LPS-induced sepsis.

Summary

Direct adhesion of neutrophils to endothelial cells via Mac-1 is required for NET formation in response to septic stimuli. Mac-1 blockade curtails NET release and ameliorates endothelial injury and lung damage in LPS sepsis, identifying Mac-1 as a tractable therapeutic target.

Key Findings

• Neutrophil adhesion to endothelial cells is essential for NET formation in response to LPS, LTA, and septic plasma.
• Blocking Mac-1 impedes NET formation, whereas inhibiting PSGL-1 or LFA-1 does not.
• Adhesion-dependent NETosis requires extracellular Ca2+ influx and PAD4-mediated histone H3 citrullination; Mac-1 blockade does not alter Ca2+ influx.
• In LPS-induced sepsis mice, Mac-1 blockade reduced NETs, inflammatory cytokines, endothelial damage, and lung injury.

Clinical Implications

Therapies inhibiting Mac-1 could reduce NET-driven endothelial injury and potentially prevent or mitigate sepsis-associated ARDS, pending safety and infection-control evaluations.

Limitations

• Relies on LPS models that may not capture the heterogeneity of clinical sepsis and ARDS.
• Survival outcomes and effects on host defense against infection were not reported.

Future Directions

Evaluate Mac-1 inhibitors in polymicrobial and pneumonia models, assess survival and infection risk, and explore translational candidates or repurposed agents targeting Mac-1.