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

• Published in: Inflammation 2020-06, Vol.43 (3), p.1054-1064
• Main Authors: Mirea, Andreea-Manuela, Stienstra, Rinke, Kanneganti, Thirumala-Devi, Tack, Cees J., Chavakis, Triantafyllos, Toonen, Erik J.M., Joosten, Leo A.B.
• Format: Article
• Language: English
• Subjects: Adipose tissue; Animals; Biomedical and Life Sciences; Biomedicine; Caspase 1 - deficiency; Caspase 1 - genetics; Caspase-1; Diet, High-Fat - adverse effects; Elastase; Fatty liver; High fat diet; IL-1β; Immunology; Inflammasomes; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Internal Medicine; Leukocyte Elastase - deficiency; Leukocyte Elastase - genetics; Liver diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - prevention & control; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - prevention & control; Original; Original Article; Pathology; Pharmacology/Toxicology; Proteinase; Proteinase 3; Rheumatology; Serine; Serine Endopeptidases - deficiency; Serine Endopeptidases - genetics; Steatosis; Transcription activation
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-020-01190-4

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.