Therapeutic Opportunities of IL-22 in Non-Alcoholic Fatty Liver Disease: From Molecular Mechanisms to Clinical Applications

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver disorders and can progress into a series of liver diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even liver cancer. Interleukin-22 (IL-22), a member of the IL-10 family of cytokines, is predominantly produced by lymphocytes but acts exclusively on epithelial cells. IL-22 was proven to favor tissue protection and regeneration in multiple diseases. Emerging evidence suggests that IL-22 plays important protective functions against NAFLD by improving insulin sensitivity, modulating lipid metabolism, relieving oxidative and endoplasmic reticulum (ER) stress, and inhibiting apoptosis. By directly interacting with the heterodimeric IL-10R2 and IL-22R1 receptor complex on hepatocytes, IL-22 activates the Janus kinase 1 (JAK1)/ signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK) pathways to regulate the subsequent expression of genes involved in inflammation, metabolism, tissue repair, and regeneration, thus alleviating hepatitis and steatosis. However, due to the wide biodistribution of the IL-22 receptor and its proinflammatory effects, modifications such as targeted delivery of IL-22 expression and recombinant IL-22 fusion proteins to improve its efficacy while reducing systemic side effects should be taken for further clinical application. In this review, we summarized recent progress in understanding the physiological and pathological importance of the IL-22-IL-22R axis in NAFLD and the mechanisms of IL-22 in the protection of NAFLD and discussed the potential strategies to maneuver this specific cytokine for therapeutic applications for NAFLD.

The Molecular Mechanism of Hepatic Lipid Metabolism Disorder Caused by NaAsO2 through Regulating the ERK/PPAR Signaling Pathway

“…The accumulation of intracellular lipids was promoted by activating the ERK signaling pathway, and the intracellular lipid content was decreased after the treatment with the ERK-specific inhibitor PD98059 [ 29 ]. Although a large number of data had been proven in the study of hepatitis [ 51 , 52 ], the role of ERK in lipid metabolism was not clear.…”

AhR Activation Leads to Attenuation of Murine Autoimmune Hepatitis: Single-Cell RNA-Seq Analysis Reveals Unique Immune Cell Phenotypes and Gene Expression Changes in the Liver

“…It enacts its effects on epithelial cells and has been shown to activate the JAK-STAT pathway (52) in addition to inhibiting apoptosis and modulating metabolic function (53). In the liver, it is well established that IL-22 plays a role in liver disease either in a protective manner, through regulation of genes involved in tissue repair, metabolism, and inflammation (54,55), or in exacerbation of disease as evidenced by upregulation in patient livers of those with chronic hepatitis B and C as well as in hepatitis B virus transgenic mice (56,57). Interestingly, gene delivery of IL-22 has been shown to prevent liver damage induced by ConA (58).…”

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

“…Other investigational drugs with potential therapeutic value in NAFLD include antileukotriene agents [ 210 ], GPCR modulators [ 211 ], anti-IL mABs [ 212 ], IL22 axis modulators [ 213 ], purinergic receptor agonists [ 214 ], antioxidants [ 215 ], antisense oligonucleotides [ 216 ], multitarget epigenetic regulators [ 217 ], and many more. A comprehensive list of drug candidates and experimental agents with evidence of hepatoprotective activity in NAFLD is given in Table 2 .…”