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

Abstract

<jats:title>Abstract</jats:title><jats:p>Interleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood. Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Specifically, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses. IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis. Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases.</jats:p><jats:sec><jats:title>Graphical Abstract</jats:title><jats:p>Our works demonstrate a critical role of IL-22 in regulating hepatocellular metabolism to treat liver injury via activating STAT3-lncRNA H19-AMPK-AKT-mTOR axis. These findings describe a novel mechanism underscoring the regulation of metabolic states of hepatocytes by IL-22 during liver injury with potentially broad therapeutic insights.</jats:p><jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="892927v1_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec>

IL‐22‐mediated renal metabolic reprogramming via PFKFB3 to treat kidney injury

“…Our results, suggesting the promotion of OXPHOS and glycolysis by IL‐22 via increasing metabolic regulators expression and glucose uptake, demonstrate that IL‐22 reverses the deteriorating metabolic states associated with the kidney injury. These observations are consistent with the renal protective functions of recombinant irisin and also in line with findings from hepatocytes, where both OXPHOS and glycolysis are needed for cellular functions, but if these are inhibited, then the primary tubule cells and hepatocytes become dysfunctional 35,36 …”

“…These observations are consistent with the renal protective functions of recombinant irisin and also in line with findings from hepatocytes, where both OXPHOS and glycolysis are needed for cellular functions, but if these are inhibited, then the primary tubule cells and hepatocytes become dysfunctional. 35,36 Mitochondrial dysfunction has emerged as the key molecular basis that integrates metabolic profiles and cell death. Herein, we illustrate that upon injury factors stimulation, TECs treatment with IL-22 had ameliorated accumulation of mitochondrial ROS and dysfunctional mitochondria as compared with the decreased mitochondrial integrity and function in control groups.…”

Interleukin-22 acts as a mitochondrial protector

“…Also, hepatic lipid metabolism such as mitochondrial fatty acid β-oxidation and de novo fatty acid synthesis are impaired under the pathological conditions 35 , 36 . In the recent issue of the Theranostics , Chen et al identified IL-22 as a mitochondrial protector to control metabolic reprogramming and the maintenance of mitochondrial fitness as the novel mechanism by which IL-22 adaptively protects against liver injury 37 . This previously unrecognized function of IL-22 was demonstrated by the measurement of the oxidative phosphorylation and glycolysis in damaged mouse hepatocytes.…”