Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice

Xu, Renfan; Tao, Anyu; Zhang, Shasha; Zhang, Muxun

doi:10.1093/abbs/gmt065

Cited by 50 publications

(42 citation statements)

References 34 publications

(32 reference statements)

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“…We found that anti-IL-17Ab treatment alleviated liver fibrosis in mice. In line with our observation, several studies recently reported that knockout or blockade of endogenous IL-17 attenuated the development of liver injury and fibrosis 37 38 . Thus, IL-17 plays a determinant role in the progression of liver fibrosis.…”

Section: Discussionsupporting

confidence: 91%

A deleterious role for Th9/IL-9 in hepatic fibrogenesis

Qin

Guo

et al. 2016

Sci Rep

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T helper 9 (Th9) cells, a recently recognized Th cell subset, are involved in autoimmune diseases. We aimed to investigate the role of Th9/interleukin-9 (IL-9) in the pathogenesis of hepatic fibrosis. Th9 and Th17 cells were quantified in chronic hepatitis B (CHB) patients with hepatic fibrosis, HBV-associated liver cirrhosis (LC) patients and healthy controls (HC). The percentages of Th9 and Th17 cells, concentrations of IL-9 and IL-17, as well as expression of IL-17, TNF-α, IL-6, IL-4, IL-21, TGF-β1 and IFN-γ were significantly increased in plasma of CHB and LC patients compared with those in HC. Splenic Th9 and Th17 cells, plasma concentrations and liver expression of IL-9 and IL-17A were significantly elevated in mice with hepatic fibrosis compared with controls. Neutralization of IL-9 in mice ameliorated hepatic fibrosis, attenuated the activation of hepatic stellate cells, reduced frequencies of Th9, Th17 and Th1 cells in spleen, and suppressed expression of IL-9, IL-17A, IFN-γ, TGF-β1, IL-6, IL-4 and TNF-α in plasma and liver respectively. Our data suggest a deleterious role of Th9/IL-9 in increasing hepatic fibrosis and exacerbating disease endpoints, indicating that Th9/IL9 based immunotherapy may be a promising approach for treating hepatic fibrosis.

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Section: Discussionsupporting

confidence: 91%

A deleterious role for Th9/IL-9 in hepatic fibrogenesis

Qin

Guo

et al. 2016

Sci Rep

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“…Previous work showed that intrahepatic IL-17 was significantly elevated in NASH patients. IL-17 could inhibit the insulin-signaling pathway and aggravate hepatocyte steatosis and the extent of liver inflammation 49, 50 . IL-22 is known to be a hepatocyte protector that could inhibit liver steatosis and liver damage 45, 51 .…”

Section: Discussionmentioning

confidence: 99%

Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota

Zhou

Pan

Shen

et al. 2017

Sci Rep

302

215

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Non-alcoholic steatohepatitis (NASH) is an epidemic metabolic disease with limited therapeutic strategies. Cumulative data support the pivotal role of gut microbiota in NASH. Here, we investigated the hypothesis regarding whether fecal microbiota transplantation (FMT) is effective in attenuating high-fat diet (HFD)-induced steatohepatitis in mice. Mice were randomized into control, HFD and HFD + FMT groups. After an 8-week HFD, FMT treatment was initiated and carried out for 8 weeks. The gut microbiota structure, butyrate concentrations of the cecal content, liver pathology and intrahepatic lipid and cytokines were examined. Our results showed that after FMT, the gut microbiota disturbance was corrected in HFD-fed mice with elevated abundances of the beneficial bacteria Christensenellaceae and Lactobacillus. FMT also increased butyrate concentrations of the cecal content and the intestinal tight junction protein ZO-1, resulting in relief of endotoxima in HFD-fed mice. Steatohepatitis was alleviated after FMT, as indicated by a significant decrease in intrahepatic lipid accumulation (reduced Oli-red staining, decreased intrahepatic triglyceride and cholesterol), intrahepatic pro-inflammatory cytokines, and the NAS score. Accordingly, intrahepatic IFN-γ and IL-17 were decreased, but Foxp3, IL-4 and IL-22 were increased after FMT intervention. These data indicate that FMT attenuated HFD-induced steatohepatitis in mice via a beneficial effect on the gut microbiota.

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“…And the neutralization or the lack of this axis caused significant attenuation of obesity, methionine choline-deficient diet (MCDD), or schistosoma-induced liver inflammation and fibrosis (15, 41, 42, 86, 104, 114). In addition, livers of IL-17(−/−) mice were protected from NASH development (42).…”

Section: Underlying Mechanisms Pathways and Relationship Between Cementioning

confidence: 99%

“…The immune imbalances underlying the evolution of NAFLD has been explored as therapeutic targets for new drugs (or pleiotropic effects of old drugs) with the potential to slow the disease progression (114, 128). …”

Section: Emerging and Potentials Therapeutics Agents Targeting The Immentioning

confidence: 99%

Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

Paquissi

2016

Front. Immunol.

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Non-alcoholic fatty liver disease (NAFLD) is an increasing problem worldwide and is associated with negative outcomes such as cirrhosis, hepatocellular carcinoma, insulin resistance, diabetes, and cardiovascular events. Current evidence shows that the immune response has an important participation driving the initiation, maintenance, and progression of the disease. So, various immune imbalances, from cellular to cytokines levels, have been studied, either for better compression of the disease pathophysiology or as biomarkers for severity assessment and outcome prediction. In this article, we performed a thorough review of studies that evaluated the role of inflammatory/immune imbalances in the NAFLD. At the cellular level, we gave special focus on the imbalance between neutrophils and lymphocytes counts (the neutrophil-to-lymphocyte ratio), and that which occurs between T helper 17 (Th17) and regulatory T cells as emerging biomarkers. By extension, we reviewed the reflection of these imbalances at the molecular level through pro-inflammatory cytokines including those involved in Th17 differentiation (IL-6, IL-21, IL-23, and transforming growth factor-beta), and those released by Th17 cells (IL-17A, IL-17F, IL-21, and IL-22). We gave particular attention to the role of IL-17, either produced by Th17 cells or neutrophils, in fibrogenesis and steatohepatitis. Finally, we reviewed the potential of these pathways as new therapeutic targets in NAFLD.

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Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice

Cited by 50 publications

References 34 publications

A deleterious role for Th9/IL-9 in hepatic fibrogenesis

A deleterious role for Th9/IL-9 in hepatic fibrogenesis

Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota

Immune Imbalances in Non-Alcoholic Fatty Liver Disease: From General Biomarkers and Neutrophils to Interleukin-17 Axis Activation and New Therapeutic Targets

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