Modulating the NLRP3 Inflammasome: Acitretin as a potential treatment for Sepsis-induced acute lung injury.

Summary

Acitretin, a clinically used retinoid, suppresses NLRP3 inflammasome activation by blocking ASC oligomerization, thereby reducing IL-1β maturation and pyroptosis. In LPS-induced sepsis models, it mitigates acute lung injury and improves survival, with effects dependent on NLRP3/GSDMD signaling.

Key Findings

• Acitretin reduced mortality and attenuated lung inflammation and edema in LPS-induced septic mice.
• Transcriptomics and in vitro assays showed suppression of the NLRP3 inflammasome pathway, with decreased IL-1β, caspase-1 p20, and GSDMD cleavage.
• Acitretin blocked ASC oligomerization and interaction with NLRP3, inhibiting inflammasome assembly.
• Protective effects were lost in Nlrp3 and Gsdmd knockout mice, confirming target dependence.

Clinical Implications

While preclinical, findings support exploring acitretin in early-phase trials for sepsis-related lung injury or hyperinflammation, with careful safety and dosing evaluation.

Limitations

• Relies on LPS-induced models; lacks polymicrobial or CLP models of sepsis.
• No pharmacokinetic/safety data in sepsis context; clinical translatability and dosing remain unknown.

Future Directions

Validate efficacy in polymicrobial sepsis (e.g., CLP), assess lung-targeted delivery, and conduct early-phase clinical trials with biomarker-guided selection (IL-1β, inflammasome signatures).