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

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 proinflammatory 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.

Dietary Erythrodiol Modifies Hepatic Transcriptome in Mice in a Sex and Dose-Dependent Way

“…Prtn3 encodes for a proteinase 3 with proteolytic activities and reactive oxygen species responses. Ptrn3 deficiency is strongly correlated with fewer incidences of liver steatosis and adipose tissue inflammation and thus reduced risk of NAFLD and obesity-related steatosis [ 35 ]. High PRTN3 levels are also correlated with poor survival rates in pancreatic cancer [ 36 ].…”

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“…IL-1beta is secreted as an inactive molecule needing a proteolytic cleavage to become bioactive. Mechanisms activating IL-1beta include the classical NLRP3 inflammasome-caspase-1 and the neutrophil serine proteases, neutrophil elastase, and proteinase-3 [ 22 ].…”

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“…Interleukin (IL)-1ß is an important mediator in immune responses of obese individuals. [14] Animal studies also reported the upregulation of this cytokine in the lungs [,15,16] as well as the activation of Nuclear Factor kappa B (NF-κB) and some proinflammatory markers. [17] Recent investigations have shown the effects of HFD feeding on lung inflammatory response, which was mediated by proinflammatory cytokines such as IL-1β, NF-κB, and IL-6.…”