The Role of IL-17 Signaling in Regulation of the Liver–Brain Axis and Intestinal Permeability in Alcoholic Liver Disease

Ma, Hsiao-Yen; Xu, Jun; Liu, Xiao; Zhu, Yunheng; Gao, Bin; Karin, Michael; Tsukamoto, Hidekazu; Jeste, Dilip V.; Grant, Igor; Roberts, Amanda J.; Contet, Candice; Geoffroy, Cédric G.; Zheng, Binhai; Brenner, David A.; Kisseleva, Tatiana

doi:10.1007/s40139-016-0097-3

Cited by 26 publications

(23 citation statements)

References 110 publications

(136 reference statements)

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“…In response to IL-1β and IL-23, γδ T cells secrete innate IL-17 to promote T-helper 17 responses in autoimmune inflammation and chronic ALD. (2,11) Moreover, binge alcohol intake specifically induces the inhibition of TLR4 signaling by heat shock protein 70 and protein phosphatase 1 but does not inhibit the TLR3-IRF3 pathways in human monocytes. (36) Furthermore, chronic and acute EtOH ingestion increases liver injury through IRF3-induced apoptosis of restorative lymphocyte antigen 6 locus C low macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…cells release various inflammatory mediators such as cytokines, chemokines, and extracellular vesicles (EVs). (1,2) EVs play important roles in intercellular communication by delivering diverse cargos, including mRNA, microRNA (miRNA), DNA, proteins, and lipids. (3,4) Depending on their size and biogenesis, they are classified into three types that include exosomes (Exos; 50-100 nm), microvesicles (MVs; 100-1,000 nm), or apoptotic bodies (500-2,000 nm).…”

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confidence: 99%

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Mitochondrial Double‐Stranded RNA in Exosome Promotes Interleukin‐17 Production Through Toll‐Like Receptor 3 in Alcohol‐associated Liver Injury

et al. 2020

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Background and Aims Mitochondrial double‐stranded RNA (mtdsRNA) and its innate immune responses have been reported previously; however, mtdsRNA generation and its effects on alcohol‐associated liver disease (ALD) remain unclear. Here, we report that hepatic mtdsRNA stimulates toll‐like receptor 3 (TLR3) in Kupffer cells through the exosome (Exo) to enhance interleukin (IL)‐17A (IL‐17A) production in ALD. Approach and Results Following binge ethanol (EtOH) drinking, IL‐17A production primarily increased in γδ T cells of wild‐type (WT) mice, whereas the production of IL‐17A was mainly facilitated by CD4+ T cells in acute‐on‐chronic EtOH consumption. These were not observed in TLR3 knockout (KO) or Kupffer cell–depleted WT mice. The expression of polynucleotide phosphorylase, an mtdsRNA‐restricting enzyme, was significantly decreased in EtOH‐exposed livers and hepatocytes of WT mice. Immunostaining revealed that mtdsRNA colocalized with the mitochondria in EtOH‐treated hepatocytes from WT mice and healthy humans. Bioanalyzer analysis revealed that small‐sized RNAs were enriched in EtOH‐treated Exos (EtOH‐Exos) rather than EtOH‐treated microvesicles in hepatocytes of WT mice and humans. Quantitative real‐time PCR and RNA sequencing analyses indicated that mRNA expression of mitochondrial genes encoded by heavy and light strands was robustly increased in EtOH‐Exos from mice and humans. After direct treatment with EtOH‐Exos, IL‐1β expression was significantly increased in WT Kupffer cells but not in TLR3 KO Kupffer cells, augmenting IL‐17A production of γδ T cells in mice and humans. Conclusions EtOH‐mediated generation of mtdsRNA contributes to TLR3 activation in Kupffer cells through exosomal delivery. Consequently, increased IL‐1β expression in Kupffer cells triggers IL‐17A production in γδ T cells at the early stage that may accelerate IL‐17A expression in CD4+ T cells in the later stage of ALD. Therefore, mtdsRNA and TLR3 may function as therapeutic targets in ALD.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Mitochondrial Double‐Stranded RNA in Exosome Promotes Interleukin‐17 Production Through Toll‐Like Receptor 3 in Alcohol‐associated Liver Injury

et al. 2020

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“…23 IL-17, which is highly elevated in ALD, likely plays a complex and detrimental role in promoting ALD disease progression by acting on many cell types including hepatocytes, non-parenchymal cells, and inflammatory cells in the liver. 76 IL-8 and CXCL1 are 2 of the most highly elevated chemokines in patients with AH and likely promote liver inflammation and injury by stimulating neutrophil infiltration. 35 Blockade of IL-8 receptor or CXCL1 ameliorated mouse ASH.…”

Section: Cytokines and Chemokinesmentioning

confidence: 99%

Inflammatory pathways in alcoholic steatohepatitis

Gao

Ahmad

Nagy

et al. 2019

Journal of Hepatology

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277

284

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Inflammatory processes are primary contributors to the development and progression of alcoholic steatohepatitis (ASH), with severe alcoholic hepatitis characterised by non-resolving inflammation. Inflammation in the progression of ASH is a complex response to microbial dysbiosis, loss of barrier integrity in the intestine, hepatocellular stress and death, as well as inter-organ crosstalk. Herein, we review the roles of multiple cell types that are involved in inflammation in ASH, including resident macrophages and infiltrating monocytes, as well as other cell types in the innate and adaptive immune system. In response to chronic, heavy alcohol exposure, hepatocytes themselves also contribute to the inflammatory process; hepatocytes express a large number of chemokines and inflammatory mediators and can also release damage-associated molecular patterns during injury and death. These cellular responses are mediated and accompanied by changes in the expression of pro-and anti-inflammatory cytokines and chemokines, as well as by signals which orchestrate the recruitment of immune cells and activation of the inflammatory process. Additional mechanisms for cell-cell and inter-organ communication in ASH are also reviewed, including the roles of extracellular vesicles and microRNAs, as well as inter-organ crosstalk. We highlight the concept that inflammation also plays an important role in promoting liver repair and controlling bacterial infection. Understanding the complex regulatory processes that are disrupted during the progression of ASH will likely lead to better targeted strategies for therapeutic interventions.

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“…The increased levels of proinflammatory cytokines are tightly associated with HSC activation . In agreement, Il‐17‐produced T cells regulate production of TGF‐β1 in Kupffer cells and can directly activate collagen type I production by HSCs, the major source of fibrogenic myofibroblasts in fibrotic liver …”

Section: Exosomes In Liver Fibrosismentioning

confidence: 87%

“…(32) In agreement, Il-17-produced T cells regulate production of TGF-β1 in Kupffer cells and can directly activate collagen type I production by HSCs, the major source of fibrogenic myofibroblasts in fibrotic liver. (33) Exosomes released from epithelial cells carry information that can activate fibroblasts and initiate and perpetuate fibrosis. For example, injured epithelial cells produce increased numbers of exosomes containing information sufficient to activate fibroblasts.…”

Section: The Pathogenesis Of Epithelial Injurymentioning

confidence: 99%

Combatting Fibrosis: Exosome‐Based Therapies in the Regression of Liver Fibrosis

2018

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Hepatic fibrosis results from chronic injury and inflammation in the liver and leads to cirrhosis, liver failure, and portal hypertension. Understanding the molecular mechanisms underlying hepatic fibrosis has advanced the prospect of developing therapies for regression of the disease. Resolution of fibrosis requires a reduction of proinflammatory and fibrogenic cytokines, a decrease in extracellular matrix (ECM) protein production, an increase in collagenase activity, and finally, a disappearance of activated myofibroblasts. Exosomes are nanovesicles of endocytic origin secreted by most cell types. They epigenetically reprogram and alter the phenotype of their recipient cells and hold great promise for the reversal of fibrosis. Recent studies have shown that exosomes function as conduits for intercellular transfer and contain all the necessary components to induce resolution of fibrosis, including the ability to (1) inhibit macrophage activation and cytokine secretion, (2) remodel ECM production and decrease fibrous scars, and (3) inactivate hepatic stellate cells, a major myofibroblast population. Here, we discuss the research involving the regression of hepatic fibrosis. We focus on the newly discovered roles of exosomes during fibrogenesis and as a therapy for fibrosis reversal. We also emphasize the novel discoveries of exosome‐based antifibrotic treatments in vitro and in vivo.

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The Role of IL-17 Signaling in Regulation of the Liver–Brain Axis and Intestinal Permeability in Alcoholic Liver Disease

Cited by 26 publications

References 110 publications

Mitochondrial Double‐Stranded RNA in Exosome Promotes Interleukin‐17 Production Through Toll‐Like Receptor 3 in Alcohol‐associated Liver Injury

Mitochondrial Double‐Stranded RNA in Exosome Promotes Interleukin‐17 Production Through Toll‐Like Receptor 3 in Alcohol‐associated Liver Injury

Inflammatory pathways in alcoholic steatohepatitis

Combatting Fibrosis: Exosome‐Based Therapies in the Regression of Liver Fibrosis

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