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Publications

Journal Article Ahead of print

PubMed: 42478233 DOI: 10.1002/advs.76587

Membrane-Active Peptide Protects Against Inflammation by Targeting NLRP3 Activation at the Trans-Golgi Network.

Adv Sci (Weinh)

Authors: Jonas Engelhardt, Nico Kirsch, Aileen Kerfin, Lars P Lunding, Dominic Ferber, Hannes Buthmann, Ilka Schreier, Carlotta Bosio, Ann-Kathrin Dobbelstein, Anna Klawonn, Rebecca C Coll, Lena Bauernhofer, Sandro Keller, Matthias Geyer, Michael Wegmann, Andra B Schromm, Günther Weindl

Affiliations

  • Pharmaceutical Institute, Section Pharmacology and Toxicology, University of Bonn, Bonn, Germany.
  • Division of Immunobiophysics, Priority Area Infections, Research Center Borstel, Leibniz Lung Center, Member of Leibniz Health Technologies, Borstel, Germany.
  • Division of Lung Immunology, Priority Area Chronic Lung Diseases, Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
  • Airway Research North (ARCN), German Center for Lung Research (DZL), Borstel, Germany.
  • Institute of Structural Biology, University of Bonn, Bonn, Germany.
  • Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
  • Biophysics, Institute of Molecular Biosciences (IMB), NAWI Graz, University of Graz, Graz, Austria.
  • Field of Excellence Biohealth, University of Graz, Graz, Austria.
  • BioTechMed-Graz, Graz, Austria.
  • Kiel Nano, Surface and Interface Science KiNSIS, Kiel University, Kiel, Germany.

Abstract

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-1β 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-1β 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.

MeSH

Biomedical Research, Macrophages, Inflammasomes, Trans-Golgi Network, Therapeutics, Asthma, Membranes