2020
DOI: 10.1002/hep.31041
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Mitochondrial Double‐Stranded RNA in Exosome Promotes Interleukin‐17 Production Through Toll‐Like Receptor 3 in Alcohol‐associated Liver Injury

Abstract: 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… Show more

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Cited by 93 publications
(76 citation statements)
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“…In this context, under mitochondrial stress, mt-dsRNAs are exported to the extracellular space where they are recognized by TLR3 receptors in the neighboring cells to induce an inflammatory response. A similar phenomenon was observed when liver cells were under acute alcoholic stress 40 , indicating that mt-dsRNAs acting as intercellular signaling molecules might be a general response to various mitochondrial stressors.…”
Section: Discussionsupporting
confidence: 63%
See 1 more Smart Citation
“…In this context, under mitochondrial stress, mt-dsRNAs are exported to the extracellular space where they are recognized by TLR3 receptors in the neighboring cells to induce an inflammatory response. A similar phenomenon was observed when liver cells were under acute alcoholic stress 40 , indicating that mt-dsRNAs acting as intercellular signaling molecules might be a general response to various mitochondrial stressors.…”
Section: Discussionsupporting
confidence: 63%
“…These mt-dsRNAs are generated due to the bidirectional transcription of the circular mitochondrial genome, which results in the transcription of long complementary RNAs 38 . Moreover, mt-dsRNAs can also activate MDA5 in mice and can be secreted in exosomes to activate TLR3 in liver cells during alcoholic stress 39,40 . Considering that the mitochondrial dysfunction is frequently reported in OA patients and that mt-dsRNAs can activate multiple PRRs to induce expression of inflammatory cytokines and apoptosis 32,39,[41][42][43] , the role of mt-dsRNAs during the onset and progression of OA needs further investigation.…”
Section: Introductionmentioning
confidence: 99%
“…Furthermore, γδ T cells may accelerate the production of IL-17A in CD4 + T cells in the later stages of ALD. 129 MAIT cells are markedly reduced in the peripheral blood of patients with severe AH and alcohol-related cirrhosis but not in the liver. 130,131 Homing signals including β7-integrins and the chemoattractant CXCL10 hyperexpressed in the liver may facilitate intrahepatic MAIT cell relocation with preferential portal accumulation in ALD.…”
Section: Viral Infectionmentioning
confidence: 92%
“…mtdsRNA has been recently recognized as a novel mtDAMP that interacts with the dsRNA sensor to trigger innate immune signaling. In an alcoholic liver disease model, hepatocytes generate exosomal mtdsRNA to mediate TLR3 activation and subsequent IL-1β expression in KC [106]. Mitochondrial N-formyl peptides were released from hepatocyte trigger formyl peptide receptor 1 on KC, subsequently stimulating NF-κB activity [5].…”
Section: Role Of Mir-29a In Oxidative Stress and Inflammationmentioning
confidence: 99%