The NLRP3 inflammasome is a multi-protein complex that plays a crucial role in inflammatory processes mediated by the innate immune system. Dysregulated NLRP3 activation has been implicated in age-related inflammatory diseases, making it a promising therapeutic target. Here, we report that the synthetic membrane-active antimicrobial peptide Pep19-2.5 directly inhibits NLRP3 inflammasome activation. Through cellular, biophysical, and biochemical analyses, we find that Pep19-2.5 suppresses NLRP3 inflammasome signaling downstream of NLRP3 activation. Pep19-2.5 interacts with macrophage membranes, supporting a membrane-targeting mechanism for its anti-inflammatory effects. Mechanistically, Pep19-2.5 binds to phosphatidylinositol (PI)-containing lipid membranes and dispersed trans-Golgi network (dTGN) structures, which could potentially affect NLRP3 recruitment to the dTGN. We demonstrate a strong and NLRP3-dependent induction of IL-1beta secretion from human macrophages by house dust mite (HDM) extract, which can be inhibited by Pep19-2.5. In line with these findings, therapeutic application of Pep19-2.5 via the nasal aerosol route reduces IL-1beta levels, eosinophil infiltration in bronchoalveolar lavage and significantly improved lung function in an in vivo HDM-mouse model of allergic airway inflammation. Our findings highlight the therapeutic potential of targeting NLRP3 activation by the small membrane-active peptide Pep19-2.5 for the treatment of NLRP3-driven inflammatory diseases.
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