Interleukin‐22 Ameliorates Neutrophil‐Driven Nonalcoholic Steatohepatitis Through Multiple Targets

Abstract

Background and Aims Nonalcoholic fatty liver disease encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. At present, how simple steatosis progresses to NASH remains obscure and effective pharmacological therapies are lacking. Hepatic expression of C‐X‐C motif chemokine ligand 1 (CXCL1), a key chemokine for neutrophil infiltration (a hallmark of NASH), is highly elevated in NASH patients but not in fatty livers in obese individuals or in high‐fat diet (HFD)‐fed mice. The aim of this study was to test whether overexpression of CXCL1 itself in the liver can induce NASH in HFD‐fed mice and to test the therapeutic potential of IL‐22 in this new NASH model. Approach and Results Overexpression of Cxcl1 in the liver alone promotes steatosis‐to‐NASH progression in HFD‐fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as apoptosis signal‐regulating kinase 1 and p38 mitogen‐activated protein kinase) activation. Myeloid cell‐specific deletion of the neutrophil cytosolic factor 1 (Ncf1)/p47phox gene, which encodes a component of the NADPH oxidase 2 complex that mediates neutrophil oxidative burst, markedly reduced CXCL1‐induced NASH and stress kinase activation in HFD‐fed mice. Treatment with interleukin (IL)‐22, a cytokine with multiple targets, ameliorated CXCL1/HFD‐induced NASH or methionine‐choline deficient diet‐induced NASH in mice. Mechanistically, IL‐22 blocked hepatic oxidative stress and its associated stress kinases via the induction of metallothionein, one of the most potent antioxidant proteins. Moreover, although it does not target immune cells, IL‐22 treatment attenuated the inflammatory functions of hepatocyte‐derived, mitochondrial DNA‐enriched extracellular vesicles, thereby suppressing liver inflammation in NASH. Conclusions Hepatic overexpression of CXCL1 is sufficient to drive steatosis‐to‐NASH progression in HFD‐fed mice through neutrophil‐derived reactive oxygen species and activation of stress kinases, which can be reversed by IL‐22 treatment via the induction of metallothionein.

Neutrophils in liver diseases: pathogenesis and therapeutic targets

“…However, mice fed a HFD only showed weak p38α activation, which upregulated genes involved in fatty acid β-oxidation that may act to compensate for hepatocyte fat accumulation. 26,27 In patients with NASH, serum NET levels are markedly increased. In an animal model of NASH, free fatty acids also stimulated the formation of NETs in vivo and in vitro.…”

Interleukin 22 in Liver Injury, Inflammation and Cancer

“…Although progress has been made in the potential mechanisms of NAFLD and in the identification and development of new therapeutic targets, many problems remain to be resolved and there are no approved therapeutic drugs [28]. IL-22 plays a particular role in alleviating the progression of NAFLD [29].…”

Obesity and binge alcohol intake are deadly combination to induce steatohepatitis: A model of high-fat diet and binge ethanol intake

“…Adenovirus-mediated overexpression of Cxcl1 significantly elevated neutrophil infiltration in the liver of mice fed an HFD for 3 months. 50 Increased neutrophil population promoted ROS production which led to an activation of apoptosis signal-regulating kinase 1 (ASK1) and p38 mitogen-activated protein kinase (MAPK), thereby activating the signaling pathways leading to apoptosis-and ER stress-induced hepatocyte death. 51 DNA damage, oxidative stress, and other intrinsic apoptotic stimuli incurred by infiltrated neutrophils activate the mitochondrial apoptotic pathway of hepatocytes.…”

“…ROS production can also disturb the protein folding process within the ER lumen by changing the redox status, which further cause ER stress. 52,53 It has been also demonstrated that infiltrated neutrophils cause hepatocyte death through p47 phox -dependent oxidative burst and subsequent activation of ROS-sensitive stress kinases such as p38 MAPK and JNK, 50 which in turn facilitates inflammatory and fibrogenic processes and exacerbates steatosis-to-NASH progression. Microarray analysis revealed that HFD/CXCL1-induced NASH possessed expression profiles of inflammatory and fibrogenic genes, which are similar to those of NASH patients, supporting the notion that Cxcl1 overexpression results in steatosis-to-NASH progression in HFD-fed mice.…”

“…Microarray analysis revealed that HFD/CXCL1-induced NASH possessed expression profiles of inflammatory and fibrogenic genes, which are similar to those of NASH patients, supporting the notion that Cxcl1 overexpression results in steatosis-to-NASH progression in HFD-fed mice. 50 Experimental models widely used to study NASH are not developed based on the molecular mechanisms that promote steatosisto-NASH progression, but mostly developed by modulating the components of diet as seen in high-fat high-cholesterol diet, methionine choline-deficient diet, and HFD-plus-chronic CCl 4 treatment. 54,55 Hepatic neutrophil infiltration is commonly observed in steatohepatitis with different etiologies including alcohol consumption and metabolic dysregulation, and thus experimental model exploiting this hallmark of steatohepatitis will better recapitulate the spectrum of NAFLD progression in human and serve as a useful tool to investigate the pathogenic mechanisms of NASH as well as a novel therapeutic target.…”