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Publications

Journal Article Ahead of print

PubMed: 41738296 DOI: 10.1093/ajrcmb/aanag029

Altered cholesterol immunometabolism activates the macrophage NLRP3-inflammasome in lung fibrosis.

Am J Respir Cell Mol Biol

Authors: Mariza Vaso, Matija Dukic, Peter Pennitz, Artür Manukyan, Scott Collum, Wanchang Lin, Catherine L Winder, Warwick B Dunn, Jonas C Schupp, Peter Braubach, Malgorzata Wygrecka, Dewei Ren, Erik E Suarez, Howard J Huang, Rahat Hussain, Bela Patel, Harry Karmouty-Quintana, Altuna Akalin, Markus Landthaler, Geraldine Nouailles, Matthias Ochs, Elena Lopez-Rodriguez, Sonia Giambelluca

Affiliations

  • Institute of Functional Anatomy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin; German Center for Lung Research (DZL), Berlin, Germany.
  • Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Berlin Institute for Medical Systems Biology of the Max-Delbrück Center (MDC-BIMSB), Berlin, Germany.
  • Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth Houston, TX, United States.
  • Centre for Metabolomics Research, Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, United Kingdom.
  • Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Hannover, Germany.
  • Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, Hannover, Germany.
  • Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.
  • Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, United States.
  • Institute of Pathology, Hannover Medical School, German Center for Lung Research (DZL) - BREATH, Hannover, Germany.
  • Center for Infection and Genomics of the Lung (CIGL), Justus-Liebig-Universität Giessen; German Center for Lung Research (DZL), Giessen, Germany.
  • Houston Methodist J.C. Walter Jr. Transplant Center, Houston Methodist hospital, Houston, TX, United States.
  • Divisions of Critical Care, Pulmonary and Sleep Medicine, Department of Internal Medicine, McGovern Medical School, UTHealth Houston, TX, United States.
  • Institut für Biologie, Humboldt Universität zu Berlin, Berlin, Germany.

Abstract

Previous research has highlighted dysregulation in lipid metabolism during lung fibrosis. However, the impact of cholesterol immunometabolism during lung fibrosis progression remains unclear but has been related to the NLRP3-inflammasome activation in cardiovascular diseases. The main objective of this work was to investigate the link between altered cholesterol metabolism and NLRP3 inflammasome activation in fibrotic lungs. Different pulmonary fibrosis patient cohorts (from 2 centers and a publicly available dataset) and a murine model of lung fibrosis (aged SP-C-/-) were included. Expression of cholesterol metabolism proteins and cholesterol content were determined in lungs from patients and bronchoalveolar lavage fluid (BALF) cells of aging SP-C-/- mice. Metabolomic and lipidomic analyses were conducted in BALF and BALF cells of SP-C-/- versus wild-type (WT) mice. NLRP3 inflammasome components were assessed by immunoblotting, ELISA, and immunofluorescence. Lung samples from fibrosis patients showed higher cholesterol content, altered cholesterol metabolism and higher IL-18 levels, compared to controls. Moreover, key genes related to inflammasome activation and cholesterol metabolism were differentially expressed in alveolar macrophages from IPF patients. Accordingly, BALF cells of SP-C-/- mice showed alteration of their cholesterol metabolism and inflammasome activation with age and fibrosis development. Lipidomic analysis pointed at cholesterol esters as potential activating agent. The molecular mechanism linking cholesterol esters to NLRP3 inflammasome and fibrosis markers was confirmed in vitro in a human macrophage model. In conclusion, altered cholesterol esterification activates the NLRP3 inflammasome in AM during pulmonary fibrosis in a murine model and fibrosis patients.

MeSH

Cells, Lung, Fibrosis, Macrophages, Inflammasomes, Cholesterol Esters, Cholesterol, Pulmonary Fibrosis, Macrophages, Alveolar, Esters