Mice Deficient in the IL-1β Activation Genes Prtn3, Elane, and Casp1 Are Protected Against the Development of Obesity-Induced NAFLD

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Andreea Manuela Mirea - , Radboud University Nijmegen, Iuliu Hatieganu University of Medicine and Pharmacy (Author)
  • Rinke Stienstra - , Radboud University Nijmegen, Wageningen University & Research (WUR) (Author)
  • Thirumala Devi Kanneganti - , St. Jude Children Research Hospital (Author)
  • Cees J. Tack - , Radboud University Nijmegen (Author)
  • Triantafyllos Chavakis - , Institute of Clinical Chemistry and Laboratory Medicine, German Center for Diabetes Research - Paul Langerhans Insitute Dresden (Partner: HMGU), German Center for Diabetes Research (DZD e.V.) (Author)
  • Erik J.M. Toonen - , Hycult Biotech (Author)
  • Leo A.B. Joosten - , Radboud University Nijmegen, Iuliu Hatieganu University of Medicine and Pharmacy (Author)

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Inflammatory pathways contribute to disease pathogenesis; however, regulation of the underlying mechanism is not completely understood. IL-1β, a pro-inflammatory cytokine, participates in the development and progression of NAFLD. To become bioactive, IL-1β requires enzymatic processing. Mechanisms that activate IL-1β include the classical NLRP3 inflammasome-caspase-1 and the neutrophil serine proteases, neutrophil elastase, and proteinase-3. Several studies have shown that both caspase-1 and the neutrophil serine proteases are important for NAFLD development. However, it is unknown whether these pathways interact and if they have a synergistic effect in promoting NAFLD. In the present study, we developed a novel and unique mouse model by intercrossing caspase-1/11 knockout mice with neutrophil elastase/proteinase-3 double knockout mice. Subsequently, these mice were examined regarding the development of high-fat diet–induced NAFLD. Our results show that mice deficient in caspase-1, neutrophil elastase, and proteinase-3 were protected from developing diet-induced weigh gain, liver steatosis, and adipose tissue inflammation when compared with controls. We conclude that pathways that process pro-IL-1β to bioactive IL-1β play an important role in promoting the development of NAFLD and obesity-induced inflammation. Targeting these pathways could have a therapeutic potential in patients with NAFLD.

Details

Original languageEnglish
Pages (from-to)1054-1064
Number of pages11
JournalInflammation
Volume43
Issue number3
Publication statusPublished - 1 Jun 2020
Peer-reviewedYes

External IDs

PubMed 32002713

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • IL-1 beta, inflammation, neutrophil serine proteases, obesity

Library keywords