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

Abstract

Background: Acitretin, a well-established dermatological drug primarily used for psoriasis treatment, has been clinically used for several decades. However, its potential role in modulating inflammation in sepsis remains unexplored.

Objective: This study seeks to explore the impact of acitretin on sepsis-induced acute lung injury (ALI) and to elucidate the underlying mechanisms involved.

Methods: In a mouse model of sepsis induced by lipopolysaccharide (LPS), we assessed the effects of acitretin on ALI. Transcriptome sequencing of lung tissue was performed to identify relevant signaling pathways. In vitro, bone marrow-derived macrophages (BMDMs) were treated with acitretin (1 μM, 5 μM and 10 μM) to evaluate its impact on NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome activation and pyroptosis. In vivo, wild-type, Nlrp3 knockout, and Gsdmd knockout mice were used to confirm the role of the NLRP3 inflammasome in mediating acitretin's effects.

Results: Acitretin significantly mitigated sepsis-induced ALI, reducing mortality in LPS-challenged mice. Transcriptome analysis revealed that acitretin suppressed the NLRP3 inflammasome pathway in lung tissue. In vitro, acitretin dose-dependently inhibited interleukin (IL)-1β release, caspase-1 p20 production, and GSDMD cleavage in BMDMs. Furthermore, acitretin inhibited inflammasome activation by preventing ASC oligomerization and its interaction with NLRP3. In vivo, acitretin reduced lung tissue inflammation, IL-1β levels in bronchoalveolar lavage fluid, and the ratio of wet to dry in wide-type mice, but these effects were abolished in Nlrp3 and Gsdmd knockout mice.

Conclusion: Acitretin demonstrated significant anti-inflammatory properties through the suppression of the NLRP3 inflammasome, suggesting its potential as a therapeutic strategy for sepsis and related complications.

Keywords: Acitretin; Acute lung injury (ALI); GSDMD; Macrophages; NLRP3 inflammasome; Pyroptosis; sepsis.