Enhanced autophagy contributes to protective effects of IL-22 against acetaminophen-induced liver injury

Abstract

Acute or acute-on-chronic liver failure is a leading cause of death in liver diseases without effective treatment. Interleukin-22 (IL-22) is currently in clinical trials for the treatment of severe alcoholic hepatitis, but the underlying mechanisms remain to be explored. Autophagy plays a critical role in alleviating liver injury. The aim of the current study is to explore the role of autophagy in IL-22-mediated hepato-protective effect against acetaminophen (APAP)-induced liver injury.Methods: A model of acute liver injury induced by APAP was used in vivo. IL-22 was administrated to the APAP-treated mice. Hepatocytes were pre-incubated with IL-22, followed by exposure to APAP for in vitro analyses.Results: IL-22 administration significantly reduced serum ALT and AST, hepatic reactive oxygen species, and liver necrosis in APAP-challenged mice. APAP treatment increased hepatic autophagosomes, which was further intensified by IL-22 co-treatment. Hepatic LC3-II was moderately upregulated after APAP administration without obvious alteration of phosphorylation of AMP-activated kinase (p-AMPK). IL-22 pretreatment significantly upregulated hepatic LC3-II and p-AMPK in APAP-treated mice. IL-22 also alleviated APAP-induced cytotoxicity and upregulated LC3-II and p-AMPK expression in cultured hepatocytes treated with APAP in vitro. When p-AMPK was blocked with compound C (an AMPK inhibitor), IL-22-mediated LC3-II conversion and protection against APAP-induced cytotoxicity was weakened.Conclusions: Enhanced AMPK-dependent autophagy contributes to protective effects of IL-22 against APAP-induced liver injury.

Fisetin Prevents Acetaminophen-Induced Liver Injury by Promoting Autophagy

“…In this study, we found APAP stimulated the ATG family ( Figure 3E). Several studies, within the context of APAP-induced autophagy, have indicated the possibility that APAP may inhibit mTOR activity and decrease cellular ATP levels to trigger AMPK activation (Ni et al, 2013;Mo et al, 2018). Therefore, we speculate that APAP activates the AMPK pathway and regulate the ATG family (Bordi et al, 2019;Xing et al, 2019).…”

Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury

“…Of note, AMPK, a vital energy sensor, regulates cell metabolism to sustain organism homeostasis [35]. Particularly, AMPK also prevents cell or tissue damage by alleviating mitochondrial dysfunction and inhibiting cell apoptosis [36][37].…”

“…Secondly, therapeutic targeting of these metabolic processes in hepatocytes therefore can be directly favorable to the prevention or treatment of liver injury diseases. Finally, with recombinant IL-22 proteins at present being explored as potential therapeutic strategies in human diseases as severe alcoholic hepatitis, graft-versus-host disease and inflammatory bowel disease, our research may have momentous clinical significances [18][19]37].…”

IL‐22 produced by Th22 cells aggravates atherosclerosis development in ApoE−/− mice by enhancing DC‐induced Th17 cell proliferation

“…In recent years, the relationship between Th22 cells and clinical disease has attracted increased attention. IL‐22 protects against multiple infections of the lungs and intestine as well as liver injury, but it also has pathogenic roles in rheumatoid arthritis and psoriasis . However, few studies have investigated the roles of Th22 cells and IL‐22 in AS.…”

“…IL-22 protects against multiple infections of the lungs and intestine as well as liver injury, but it also has pathogenic roles in rheumatoid arthritis and psoriasis. [29][30][31][32][33] However, few studies have investigated the roles of Th22 cells and IL-22 in AS. Our previous study revealed significant increases in the peripheral Th22 cell numbers and IL-22 levels of patients with acute coronary syndrome (ACS) compared to patients with stable angina pectoris (SAP) and control patients, suggesting that the circulating Th22-type response may have a potential role in the onset of ACS symptoms.…”