IL-17A-induced NETs are profibrogenic in mice with metabolic dysfunction-associated steatotic liver disease (MASLD)

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing epidemic with limited therapeutic options. Interleukin (IL)-17A, a proinflammatory cytokine produced by both innate and adaptive immune cells, has been implicated in MASLD-related inflammation and fibrosis. Although many studies have focused on IL-17A-producing lymphocytes, the role of innate immune cells like neutrophils recruited in response to and capable of producing IL-17A, is less well-characterized. Additionally, neutrophil extracellular traps (NETs), are observed in different chronic liver diseases and correlate with disease severity. Here, we sought to determine the kinetics of IL-17A-producing neutrophils during MASLD-related fibrosis and examine the effect of IL-17 on NET formation, contributing as such to liver fibrosis. Using a mouse model of MASLD induced by high-fat diet (HFD) feeding for 15 or 30 weeks (WK) and in vitro studies, we observed a significant increase in intrahepatic IL-17A-producing neutrophils and NET formation in mice fed the HFD for 30 WK as compared to mice on HFD for 15 WK or controls. NET formation was strongly associated with liver injury and advanced fibrosis. Importantly, treatment with IL-17A induced NET formation in isolated neutrophils. IL-17A-induced NETs activated hepatic stellate cells (HSCs), induced expression of fibrogenic genes, and enhanced their migration in a wound-healing assay. All these are critical processes in fibrosis development. In conclusion, our results suggest that IL-17A-producing neutrophils, via the triggering of NET formation, play a key profibrogenic role in MASLD.