NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis

Article4 October 2022 Transparent process NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis Benedikt Kaufmann Benedikt Kaufmann Department of Pediatrics, University of California San Diego, La Jolla, California, USA Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical, University of Munich, Munich, Germany Contribution: Conceptualization, Resources, Data curation, Formal analysis, Funding acquisition, ​Investigation, Methodology, Writing - original draft, Writing - review & editing Search for more papers by this author Aleksandra Leszczynska Aleksandra Leszczynska Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author Agustina Reca Agustina Reca Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author Laela M Booshehri Laela M Booshehri Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author Janset Onyuru Janset Onyuru orcid.org/0000-0003-3924-8487 Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author ZheHao Tan ZheHao Tan Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author Alexander Wree Alexander Wree Department of Hepatology and Gastroenterology, Charité, Universitätsmedizin Berlin, Berlin, Germany Contribution: Supervision Search for more papers by this author Helmut Friess Helmut Friess Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical, University of Munich, Munich, Germany Contribution: Supervision Search for more papers by this author Daniel Hartmann Daniel Hartmann Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical, University of Munich, Munich, Germany Contribution: Supervision Search for more papers by this author Bettina Papouchado Bettina Papouchado Department of Pathology, University of California San Diego, La Jolla, California, USA Contribution: Formal analysis, ​Investigation Search for more papers by this author Lori Broderick Lori Broderick Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Resources, Supervision, Writing - review & editing Search for more papers by this author Hal M Hoffman Hal M Hoffman Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Resources, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Ben A Croker Ben A Croker Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Resources, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Yanfang Peipei Zhu Yanfang Peipei Zhu Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Ariel E Feldstein Corresponding Author Ariel E Feldstein [email protected] orcid.org/0000-0001-7202-3840 Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Conceptualization, Resources, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Benedikt Kaufmann Benedikt Kaufmann Department of Pediatrics, University of California San Diego, La Jolla, California, USA Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical, University of Munich, Munich, Germany Contribution: Conceptualization, Resources, Data curation, Formal analysis, Funding acquisition, ​Investigation, Methodology, Writing - original draft, Writing - review & editing Search for more papers by this author Aleksandra Leszczynska Aleksandra Leszczynska Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author Agustina Reca Agustina Reca Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author Laela M Booshehri Laela M Booshehri Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author Janset Onyuru Janset Onyuru orcid.org/0000-0003-3924-8487 Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author ZheHao Tan ZheHao Tan Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Data curation, ​Investigation Search for more papers by this author Alexander Wree Alexander Wree Department of Hepatology and Gastroenterology, Charité, Universitätsmedizin Berlin, Berlin, Germany Contribution: Supervision Search for more papers by this author Helmut Friess Helmut Friess Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical, University of Munich, Munich, Germany Contribution: Supervision Search for more papers by this author Daniel Hartmann Daniel Hartmann Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical, University of Munich, Munich, Germany Contribution: Supervision Search for more papers by this author Bettina Papouchado Bettina Papouchado Department of Pathology, University of California San Diego, La Jolla, California, USA Contribution: Formal analysis, ​Investigation Search for more papers by this author Lori Broderick Lori Broderick Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Resources, Supervision, Writing - review & editing Search for more papers by this author Hal M Hoffman Hal M Hoffman Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Resources, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Ben A Croker Ben A Croker Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Resources, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Yanfang Peipei Zhu Yanfang Peipei Zhu Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Ariel E Feldstein Corresponding Author Ariel E Feldstein [email protected] orcid.org/0000-0001-7202-3840 Department of Pediatrics, University of California San Diego, La Jolla, California, USA Contribution: Conceptualization, Resources, Supervision, Funding acquisition, ​Investigation, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Author Information Benedikt Kaufmann1,2, Aleksandra Leszczynska1, Agustina Reca1, Laela M Booshehri1, Janset Onyuru1, ZheHao Tan1, Alexander Wree3, Helmut Friess2, Daniel Hartmann2, Bettina Papouchado4, Lori Broderick1, Hal M Hoffman1, Ben A Croker1, Yanfang Peipei Zhu1,† and Ariel E Feldstein *,1,† 1Department of Pediatrics, University of California San Diego, La Jolla, California, USA 2Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical, University of Munich, Munich, Germany 3Department of Hepatology and Gastroenterology, Charité, Universitätsmedizin Berlin, Berlin, Germany 4Department of Pathology, University of California San Diego, La Jolla, California, USA † These authors contributed equally to this work *Corresponding author. Tel: +1 858 966 8907; E-mail: [email protected] EMBO Reports (2022)23:e54446https://doi.org/10.15252/embr.202154446 See also: KW Chen (November 2022), UC Frising et al (July 2022) Full textView the full text of the articlePDFDownload PDF of article text and main figures.PDF PLUSDownload PDF of article text, main figures, expanded view figures and appendix. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Sterile inflammation is a central element in liver diseases. The immune response following injurious stimuli involves hepatic infiltration of neutrophils and monocytes. Neutrophils are major effectors of liver inflammation, rapidly recruited to sites of inflammation, and can augment the recruitment of other leukocytes. The NLRP3 inflammasome has been increasingly implicated in severe liver inflammation, fibrosis, and cell death. In this study, the role of NLRP3 activation in neutrophils during liver inflammation and fibrosis was investigated. Mouse models with neutrophil-specific expression of mutant NLRP3 were developed. Mutant mice develop severe liver inflammation and lethal autoinflammation phenocopying mice with a systemic expression of mutant NLRP3. NLRP3 activation in neutrophils leads to a pro-inflammatory cytokine and chemokine profile in the liver, infiltration by neutrophils and macrophages, and an increase in cell death. Furthermore, mutant mice develop liver fibrosis associated with increased expression of pro-fibrogenic genes. Taken together, the present work demonstrates how neutrophils, driven by the NLRP3 inflammasome, coordinate other inflammatory myeloid cells in the liver, and propagate the inflammatory response in the context of inflammation-driven fibrosis. Synopsis Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation-driven fibrosis. Neutrophil-specific NLRP3 activation leads to liver inflammation and lethal autoinflammation. NLRP3 activation in neutrophils induces pro-inflammatory cytokine and chemokine profiles in the liver. NLRP3 activation in neutrophils leads to liver infiltration by neutrophils and macrophages, and an increase in cell death. Neutrophil-specific NLRP3 activation results in liver fibrosis associated with increased expression of pro-fibrogenic genes. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 23,Issue 11,07 November 2022This month's cover highlights the article Human‐specific ARHGAP11B ensures human‐like basal progenitor levels in hominid cerebral organoids by Jan Fischer, Eduardo Fernández Ortuño, Fabio Marsoner, Michael Heide and colleagues. The cover illustrates that ectopic expression of human ARHGAP11B in chimpanzee cerebral organoids (blue +ARHGAP11B mirror) leads to increased basal progenitor levels � one hallmark of neocortex expansion (blue chimpanzee brain). Loss of ARHGAP11B or inhibition of ARHGAP11B�s function in human cerebral organoids (magenta -ARHGAP11B mirror) leads to reduced basal progenitor levels � indicative for a reduced neocortex size (magenta human brain). (Cover concept by the authors. Cover illustration by DrawImpacts (https://www.drawimpacts.com.) Volume 23Issue 117 November 2022In this issue RelatedDetailsLoading ...