IL‑22 alleviates the fibrosis of hepatic stellate cells via the inactivation of NLRP3 inflammasome signaling

Abstract

Persistent and progressive liver injury causes liver fibrosis due to the inability of the liver to regenerate. Interleukin (IL)-22 serves an important role in liver fibrosis. However, the underlying mechanism by which IL-22 exerts its effects on liver fibrosis has not been fully elucidated. The aim of the present study was to investigate the underlying mechanism by which IL-22 affects the development of liver fibrosis. Following activation of the hepatic stellate cells (HSCs) using transforming growth factor β (TGF-β), HSC proliferation was measured using the Cell Counting Kit-8 assay. The indicators of oxidative stress were detected using specific kits. In addition, the mRNA and protein expression levels of fibrosis-associated genes were determined using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Subsequently, the protein expression levels of the NOD-like receptor protein 3 (NLRP3), caspase-1 and IL-1β were examined using western blotting. Following addition of Nigericin, a NLRP3 activator, the levels of oxidative stress and fibrosis were measured. IL-22 increased the viability of HSCs, which were activated by TGF-β. The malondialdehyde content was significantly decreased, whereas superoxide dismutase and glutathione levels were increased following IL-22 treatment. Moreover, IL-22 markedly downregulated the expression levels of fibrosis-associated genes, including α-smooth muscle actin, type I collagen and TIMP metallopeptidase inhibitor 1. Furthermore, the expression levels of NLRP3, caspase-1 and IL-1β were decreased in the IL-22-treated groups. However, the NLRP3 activator Nigericin reversed the inhibitory effects of IL-22 on the induction of oxidative stress and fibrosis of HSCs induced by TGF-β. In conclusion, the present study indicated that IL-22 alleviated the fibrosis of HSCs by inactivation of NLRP3 inflammasome signaling, which may provide further insight on the underlying mechanism by which IL-22 exerts protective effects on liver fibrosis.

Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis

“…Our proteomics analysis demonstrates IL-22-ScFv drives a complex modulation of metabolic pathways associated with the reduction in lipid accumualtion, which would require much further experimental work to ascertain relative importance of individual proteins. Overexpression of IL-22 by gene targeting or delivery through adenovirus expressing IL-22 has previously been shown to reduce liver fibrosis and accelerate fibrosis resolution during recovery in the carbon tetrachloride (CCl 4 ) model 19 , 24 . We used multiple independent preclinical MASH models to assess the effect of IL-22-ScFv, as all models reflect different aspects of human MASH 25 .…”

Role of the IL-33/ST2 Activation Pathway in the Development of the Hepatic Fibrosis Induced by Schistosoma mansoni Granulomas in Mice

“…Yet, unlike IL-10, which acts on immune cells, such as macrophages and T cells, IL-22 performs its function in tissue cells, such as hepatocytes [ 56 , 57 ]. During inflammatory processes, IL-22 directly protects the host tissue from destructive damage from the exacerbated immune response; in the liver, this cytokine promotes repair and tissue regeneration by stimulating the proliferation and survival of hepatocytes [ 57 , 58 , 59 ]. Aside from the possible role in tissue repairing, IL-22 and IL-10 may also play an important role in the modulation of liver fibrosis, decreasing HSC activation and tissue inflammation [ 59 , 60 , 61 ].…”

“…During inflammatory processes, IL-22 directly protects the host tissue from destructive damage from the exacerbated immune response; in the liver, this cytokine promotes repair and tissue regeneration by stimulating the proliferation and survival of hepatocytes [ 57 , 58 , 59 ]. Aside from the possible role in tissue repairing, IL-22 and IL-10 may also play an important role in the modulation of liver fibrosis, decreasing HSC activation and tissue inflammation [ 59 , 60 , 61 ]. Interestingly, as demonstrated in our previous articles [ 50 ], ST2 −/− mice also showed a reduction in IL-10 levels from the acute to the chronic phase of the infection, which may also be associated with the exacerbated inflammatory response developed by this strain.…”

Hederagenin inhibits high glucose‐induced fibrosis in human renal cells by suppression of NLRP3 inflammasome activation through reducing cathepsin B expression

“…Nigericin, a K + /H + ionophore, induces K + efflux to activate NLRP3 inflammasome and usually acts as a canonical NLRP3 activator (Katsnelson et al, 2015; Muñoz‐Planillo et al, 2013). Nigericin was reported to reverse the inhibitory effect of interleukin‐22 on transforming growth factor β‐induced fibrosis of hepatic stellate cells (Xing et al, 2021). Nigericin treatment aggravated lipopolysaccharide‐induced fibrosis of human renal proximal tubule epithelial cells (Xie et al, 2023).…”