Alterations in Intestinal Microbiota Lead to Production of Interleukin 17 by Intrahepatic γδ T-Cell Receptor–Positive Cells and Pathogenesis of Cholestatic Liver Disease

Tedesco, Dana; Thapa, Manoj; Chin, Chui Yoke; Ge, Yong; Gong, Minghao; Li, Jing; Gumber, Sanjeev; Speck, Patrick; Elrod, Elizabeth; Burd, Eileen M.; Kitchens, William H.; Magliocca, Joseph F.; Adams, Andrew; Weiss, David S.; Mohamadzadeh, Mansour; Grakoui, Arash

doi:10.1053/j.gastro.2018.02.019

Cited by 111 publications

(90 citation statements)

References 50 publications

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“…IL-17A has profibrogenic functions through recruitment of proinflammatory monocytes, increased production of TGF-, and enhanced TGF- responses in HSCs (6)(7)(8)(9)(10). IL-22 is hepatoprotective during acute liver injury (11,12), but its function during chronic injury is controversial.…”

Section: Introductionmentioning

confidence: 99%

Type 3 cytokines IL-17A and IL-22 drive TGF-β–dependent liver fibrosis

et al. 2018

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Inflammatory immune cells can modulate activation of hepatic stellate cells (HSCs) and progression of liver fibrosis. Type 3 inflammation characterized by production of interleukin-17A (IL-17) and IL-22 by innate and adaptive immune cells is implicated in many inflammatory conditions of the gut and can be counteracted by regulatory T cells (Tregs), but its contribution to liver fibrosis is still poorly understood. Here, we evaluated the contribution of type 3 inflammation in liver fibrosis using clinical liver biopsies, in vitro stimulation of primary HSCs, and in vivo mouse models. We report dysregulated type 3 responses in fibrotic lesions with increased IL-17+CD4+/FOXP3hiCD4+ratio and increased IL-17 and IL-22 production in advanced liver fibrosis. Neutrophils and mast cells were the main sources of IL-17 in situ in humans. In addition, we demonstrate a new profibrotic function of IL-22 through enhancement of transforming growth factor–β signaling in HSCs in a p38 mitogen-activated protein kinase–dependent manner. In vivo, IL-22RA1 knockout mice exhibited reduced fibrosis in response to thioacetamide and carbon tetrachloride. Blocking either IL-22 or IL-17 production using aryl hydrocarbon receptor or RAR-related orphan receptor gamma-t antagonists resulted in reduced fibrosis. Together, these data have identified a pathogenic role for type 3 immune response mediated by IL-22 in driving liver fibrosis during chronic liver injury.

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Section: Introductionmentioning

confidence: 99%

Type 3 cytokines IL-17A and IL-22 drive TGF-β–dependent liver fibrosis

et al. 2018

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“…In addition, the involvement of Th17 cells and IL-17 has been reported in several animal models of NAFLD progressing to NASH (27-31). Tedesco et al (32) reported the devel-opment of liver fibrosis and inflammation requires hepatic activation of γδ TCR + cells and production of IL-17 mediated by exposure to Lactobacillus gasseri that is translocated to the liver due to increased intestinal permeability in Mdr2 −/− mice. It is thought that dysbiosis, which is one of the pathogeneses of NASH, causes the proliferation and activation of Th17 cells and induces the overproduction of IL-17, thereby leading to autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin G4-related Liver Disease Overlapping with Non-alcoholic Steatohepatitis That Was Diagnosed Simultaneously with Autoimmune Pancreatitis: A Case Report and Review of the Literature

et al. 2019

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A 70-year-old woman was referred to our hospital due to symptoms of dry eyes, dry mouth, and epigastric pain. Computed tomography showed distal pancreatic swelling, liver edge dullness and surface irregularities. Serum anti-nuclear antibody titers, immunoglobulin G and IgG4 levels were elevated. Autoimmune pancreatitis (AIP) was diagnosed based on endoscopic findings and a histopathological examination. Her AIP improved after starting prednisolone treatment. A liver biopsy revealed interface hepatitis with lymphoplasmacyte and IgG4-positive plasma cell infiltration. In addition, non-alcoholic steatohepatitis (NASH) was diagnosed based on the presence of parenchymal steatosis, ballooning hepatocytes, and pericellular fibrosis. We experienced a unique liver disease case showing IgG4-related liver disease overlapping with NASH.

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“…Enrichment of intestinal Lactobacillus was found in mice with liver injury induced by acute concanavalin A (Con A) treatment, which can prevent further liver inflammation through activation of IL-22 production [38]. Furthermore, conflicting evidence supporting either a detrimental [39,40] or beneficial [14,41] effect of GM can be found for the liver injury in the ATP-binding cassette, sub-family B (MDR/TAP), member 4 (Mdr2) knockout (Mdr2 -/-) mice.…”

Section: Gut Dysbiosis Can Be An Adaptive Response To Liver Injurymentioning

confidence: 99%

Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling

Yan

Khambu

Chen

et al. 2020

Preprint

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Objective:The gut microbiota (GM) can have complicated and often undetermined interactions with the function of many organs in the body. GM is altered in a variety of liver diseases, but the significance of such changes on the liver disease is still unclear. Hepatic autophagy deficiency causes liver injury accompanied with cholestasis. Here, we investigated the impact of such hepatic changes on GM and in turn the effect of gut dysbiosis on liver injury. Design:Fecal microbiota from mice with liver-specific loss of autophagy-related gene 5 (Atg5), Atg5 ∆hep mice, were analyzed by 16S sequencing. Antibiotics (ABX) was used to modulate GM in mice.Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice overexpressing FGF15 gene, or given a fibroblast growth factor receptor 4 (FGFR4) inhibitor. Results:The composition of GM was significantly changed with a notable increase of BA-metabolizing bacteria in Atg5 ∆hep mice, leading to a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs in the intestine, which markedly activated ileal FXR with an increased expression of FGF15. ABX or cholestyramine treatment exacerbated liver injury and ductular reaction, and decreased FGF15 expression, whereas modulating FGF15 signaling altered liver phenotypes in the autophagy-deficient mice. Conclusion:Gut dysbiosis can remedy liver injury in Atg5 ∆hep mice through the FXR-FGF15 signaling.Antibiotics use in the condition of liver injury may have unexpected adverse consequences via the gutliver axis.

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Alterations in Intestinal Microbiota Lead to Production of Interleukin 17 by Intrahepatic γδ T-Cell Receptor–Positive Cells and Pathogenesis of Cholestatic Liver Disease

Abstract: In Mdr2 mice, we found development of liver fibrosis and inflammation to require hepatic activation of γδ TCR cells and production of IL17 mediated by exposure to L gasseri. This pathway appears to contribute to development of cholestatic liver disease in patients.

Cited by 111 publications

References 50 publications

Type 3 cytokines IL-17A and IL-22 drive TGF-β–dependent liver fibrosis

Type 3 cytokines IL-17A and IL-22 drive TGF-β–dependent liver fibrosis

Immunoglobulin G4-related Liver Disease Overlapping with Non-alcoholic Steatohepatitis That Was Diagnosed Simultaneously with Autoimmune Pancreatitis: A Case Report and Review of the Literature

Gut dysbiosis protects against liver injury in autophagy deficient mice by FXR-FGF15 feedback signaling

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