IL‐17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice

Harley, Isaac T.W.; Stankiewicz, Traci E.; Giles, Daniel; Softic, Samir; Flick, Leah M.; Cappelletti, Monica; Sheridan, Rachel; Xanthakos, Stavra A.; Steinbrecher, Kris A.; Sartor, R. Balfour; Kohli, Rohit; Karp, Christopher L.; Divanovic, Senad

doi:10.1002/hep.26746

Cited by 214 publications

(264 citation statements)

References 43 publications

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“…In mice on HFD, the lack of Gal-3 resulted in lower levels of IL-17 in liver. Recent evidence shows that activation of the IL-17 axis in obesitydriven NAFLD has an important role in the progression of liver steatosis to NASH (30). The data of attenuated liver inflammation in LGALS3 -/-mice fed obesogenic HFD in this study are in agreement with the data in the study of the atherogenic diet model of NASH (15).…”

Section: Discussionsupporting

confidence: 91%

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Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

Jeftic

Jovičić

Pantic

et al. 2015

Mol Med

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The importance of Galectin-3 (Gal-3) in obesity-associated liver pathology is incompletely defined. To dissect the role of Gal-3 in fibrotic nonalcoholic steatohepatitis (NASH), Gal-3-deficient (LGALS3 -/-) and wild-type (LGALS3 +/+ ) C57Bl/6 mice were placed on an obesogenic high fat diet (HFD, 60% kcal fat) or standard chow diet for 12 and 24 wks. Compared to WT mice, HFD-fed LGALS3 -/-mice developed, in addition to increased visceral adiposity and diabetes, marked liver steatosis, which was accompanied with higher expression of hepatic PPAR-γ, Cd36, Abca-1 and FAS. However, as opposed to LGALS3 -/-mice, hepatocellular damage, inflammation and fibrosis were more extensive in WT mice which had an elevated number of mature myeloid dendritic cells, proinflammatory CD11b + Ly6C hi monocytes/macrophages in liver, peripheral blood and bone marrow, and increased hepatic CCL2, F4/80, CD11c, TLR4, CD14, NLRP3 inflammasome, IL-1β and NADPH-oxidase enzymes mRNA expression. Thus, obesitydriven greater steatosis was uncoupled with attenuated fibrotic NASH in Gal-3-deficient mice. HFD-fed WT mice had a higher number of hepatocytes that strongly expressed IL-33 and hepatic CD11b genotypes, albeit to a significantly lower extent in LGALS3 -/-mice, which was associated with less numerous hepatic IL-13-expressing CD11b + cells. The present study provides evidence of a novel role for Gal-3 in regulating IL-33-dependent liver fibrosis. adipose tissue and islets where dendritic cells (DCs) and macrophages play important roles (11). The data on the effect of Gal-3 ablation in liver steatosis/inflammation are controversial. Nomoto et al. (13) showed that Gal-3-deficient mice spontaneously developed steatosis at six months of age and that a lack of Gal-3 led to greater steatosis and liver injury in the model of CDAA diet-induced NASH (14). On the other hand, in a study by Iacobini et al. (15) Gal-3 null mice fed an atherogenic diet were resistant to the development of steatosis and NASH. In the liver, Gal-3 is highly expressed in Kupffer cells and its expression is increased during hepatocellular damage (16). The essential step in hepatic inflammation and fibrogenesis is CCL2-mediated monocyte recruitment (17,18). Resident and recruited liver macrophages may be polarized toward classically activated macrophages (M1), which promote survival of hepatic myofibroblasts by secreted TNF-α and IL-1β, and, alternatively, macrophages that express the Th2-type cytokines (M2), including IL-13, which directly stimulates collagen synthesis in myofibroblasts (19)(20)(21). Macrophage-derived Gal-3 has been shown to promote myofibroblast activation in liver fibrosis (22,23). The disruption of the Gal-3 gene was reported to block TGF-β mediated myofibroblast activation and procollagen expression and markedly attenuated CCl 4 -induced liver fibrosis in mice (22). Interleukin-33 (IL-33), a damage-associated molecular pattern (DAMP) molecule, could induce IL-13 production by macrophages to promote type 2 immunity (24). IL-33 has a profibrogenic role ...

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Section: Discussionsupporting

confidence: 91%

“…Paraffin-embedded liver and colon sections (5 μm) were stained with H&E for the assessment of the degree of inflammation (29,30). Oil red O staining was used to assess hepatic lipid deposition.…”

Section: Histopathological Analysesmentioning

confidence: 99%

Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

Jeftic

Jovičić

Pantic

et al. 2015

Mol Med

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“…In morbidly obese adult patients, hepatic upregulation of various genes involved in immune regulation and T cell activation toward a Th1 phenotype were described, however, without characterizing the leukocytic infiltrate (25). Interestingly, an upregulation of these inflammatory genes was already observed in six patients with showed weight gain and hepatic triglyceride accumulation but no development of steatohepatitis (9). Based on recent insights from mice and human studies, our focus was on the analysis of Th17 cells and Tregs (8).…”

Section: Discussionmentioning

confidence: 99%

Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver

Rau

Schilling

Meertens

et al. 2016

The Journal of Immunology

234

239

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Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4+ effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4+CD45RA+CD25++) and higher frequencies of IFN-γ+ and/or IL-4+ cells were detected among CD4+ T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17+ cells among intrahepatic CD4+ T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17+ cells among intrahepatic CD4+ T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.

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“…Visceral obesity induces several cytokines including the inflammatory cytokine IL-17 [82] , which induces neutrophil chemokine expression via IL-17 receptor A which is extensively expressed in the liver. Controlling the IL17related pathway effectively prevents NASH progression in mouse models [83] .…”

Section: Mechanisms Of Hcv-related Hcc and Involvement Of Oxidative Smentioning

confidence: 99%

Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

Takaki

Yamamoto

2015

WJH

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stress, causing a high rate of hepatocarcinogenesis among patients with cirrhosis. Non-alcoholic steatohepatitis is also associated with oxidative stress although its hepatocarcinogenic potential is lower than that of chronic hepatitis C. Analyses of serum markers and histological findings have shown that hepatocellular carcinoma correlates with oxidative stress and experimental data indicate that oxidative stress increases the likelihood of developing hepatocarcinogenesis. However, the results of antioxidant therapy have not been favorable. Physiological oxidative stress is a necessary biological response, and thus adequate control of oxidative stress and a balance between oxidative and anti-oxidative responses is important. Several agents including metformin and L-carnitine can reportedly control mechanistic oxidative stress. This study reviews the importance of oxidative stress in hepatocarcinogenesis and of control strategies for the optimal survival of patients with CLD and hepatocellular carcinoma. Core tip: Oxidative stress is a key biological response that correlates with the progression of chronic liver disease. However, oxidative stress is an essential survival mechanism and thus to erase it is an unsuitable approach to disease control. As hepatocarcinogenesis is closely associated with increased oxidative stress via viral proteins or chronic inflammation and lipids, controlling oxidative stress should be effective against progressive liver disease. Agents that can control oxidative stress might represent a more effective approach than reactive oxygen species-scavenging agents. AbstractOxidative stress is becoming recognized as a key factor in the progression of chronic liver disease (CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as sources of reactive oxygen species, which are apparently responsible for the initiation of necroinflammation. As a result, CLD could be a major inducer of oxidative stress. Chronic hepatitis C is a powerful generator of oxidative REVIEWSubmit a

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IL‐17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice

Cited by 214 publications

References 43 publications

Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

Galectin-3 Ablation Enhances Liver Steatosis, but Attenuates Inflammation and IL-33-Dependent Fibrosis in Obesogenic Mouse Model of Nonalcoholic Steatohepatitis

Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver

Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

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