{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T18:10:27Z","timestamp":1786817427969,"version":"build-2736575974"},"reference-count":127,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>TIR domain-containing adaptor inducing IFN-\u03b2 (TRIF) is a crucial adaptor molecule downstream of toll-like receptors 3 (TLR3) and 4 (TLR4). TRIF directly binds to TLR3 through its TIR domain, while it associates with TLR4 indirectly through the bridge adaptor molecule TRIF-related adaptor molecule (TRAM). TRIF plays a pivotal role in regulating interferon beta 1 (IFN-\u03b2) response, nuclear factor kappa B (NF-\u03baB) signaling, apoptosis, and necroptosis signaling mediated by TLR3 and TLR4. It accomplishes these by recruiting and activating various kinases or transcription factors via its distinct domains. In this review, we comprehensively summarize the TRIF-dependent signaling pathways mediated by TLR3 and TLR4, elucidating key target molecules and downstream pathways. Furthermore, we provide an overview of TRIF\u2019s impact on several liver disorders, including drug-induced liver injury, ischemia-reperfusion liver injury, autoimmune hepatitis, viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We also explore its effects on liver steatosis, inflammation, fibrosis, and carcinogenesis. A comprehensive understanding of the TRIF-dependent signaling pathways, as well as the intricate relationship between TRIF and liver diseases, can facilitate the identification of potential drug targets and the development of novel and effective therapeutics against hepatic disorders.<\/jats:p>","DOI":"10.3389\/fcell.2024.1370042","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T04:54:36Z","timestamp":1713329676000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":39,"title":["TRIF-dependent signaling and its role in liver diseases"],"prefix":"10.3389","volume":"12","author":[{"given":"Lilin","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilu","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huikuan","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.clinre.2012.11.005","article-title":"Reduced expression of TRIF in chronic HBV infected Iranian patients","volume":"37","author":"Ayoobi","year":"2013","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1152\/physrev.00040.2009","article-title":"NF-kappaB signaling: a tale of two pathways in skeletal myogenesis","volume":"90","author":"Bakkar","year":"2010","journal-title":"Physiol. Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1038\/s41423-020-00630-3","article-title":"Necroptosis, pyroptosis and apoptosis: an intricate game of cell death","volume":"18","author":"Bertheloot","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1083\/jcb.151.7.1353","article-title":"Localized biphasic changes in phosphatidylinositol-4,5-bisphosphate at sites of phagocytosis","volume":"151","author":"Botelho","year":"2000","journal-title":"J. Cell Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1002\/hep.29078","article-title":"Central role of the TIR-domain-containing adaptor-inducing interferon-\u03b2 (TRIF) adaptor protein in murine sterile liver injury","volume":"65","author":"Brempelis","year":"2017","journal-title":"Hepatology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1146\/annurev-immunol-032414-112240","article-title":"Innate immune pattern recognition: a cell biological perspective","volume":"33","author":"Brubaker","year":"2015","journal-title":"Annu. Rev. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.molimm.2014.06.033","article-title":"Toll-like receptor signalling through macromolecular protein complexes","volume":"63","author":"Bryant","year":"2015","journal-title":"Mol. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"6629","DOI":"10.4049\/jimmunol.0901033","article-title":"Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection","volume":"183","author":"Cai","year":"2009","journal-title":"J. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"5690","DOI":"10.1111\/jcmm.17599","article-title":"Polyguanine alleviated autoimmune hepatitis through regulation of macrophage receptor with collagenous structure and TLR4-TRIF-NF-\u03baB signalling","volume":"26","author":"Cai","year":"2022","journal-title":"J. Cell Mol. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"eaal3336","DOI":"10.1126\/scisignal.aal3336","article-title":"TRIF-dependent Toll-like receptor signaling suppresses Scd1 transcription in hepatocytes and prevents diet-induced hepatic steatosis","volume":"10","author":"Chen","year":"2017","journal-title":"Sci. Signal"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1007\/s10565-022-09725-1","article-title":"The role of NADPH oxidase 1 in alcohol-induced oxidative stress injury of intestinal epithelial cells","volume":"39","author":"Chen","year":"2023","journal-title":"Cell Biol. Toxicol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1111\/j.1600-065X.2012.01108.x","article-title":"Ubiquitination in signaling to and activation of IKK","volume":"246","author":"Chen","year":"2012","journal-title":"Immunol. Rev."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2589","DOI":"10.1084\/jem.20060929","article-title":"A role for IRF3-dependent RXRalpha repression in hepatotoxicity associated with viral infections","volume":"203","author":"Chow","year":"2006","journal-title":"J. Exp. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"101143","DOI":"10.1016\/j.mam.2022.101143","article-title":"The subversion of toll-like receptor signaling by bacterial and viral proteases during the development of infectious diseases","volume":"88","author":"Ciaston","year":"2022","journal-title":"Mol. Asp. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1007\/s00018-020-03656-y","article-title":"TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling","volume":"78","author":"Ciesielska","year":"2021","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"B16","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.jhep.2023.04.023","article-title":"Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation","volume":"79","author":"Colasanti","year":"2023","journal-title":"J. Hepatol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2372","DOI":"10.1073\/pnas.1018515108","article-title":"Unexpected protective role for Toll-like receptor 3 in the arterial wall","volume":"108","author":"Cole","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1038\/cdd.2014.70","article-title":"RIPK1- and RIPK3-induced cell death mode is determined by target availability","volume":"21","author":"Cook","year":"2014","journal-title":"Cell Death Differ."},{"key":"B19","doi-asserted-by":"publisher","first-page":"36560","DOI":"10.1074\/jbc.M506831200","article-title":"Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation","volume":"280","author":"Cusson-Hermance","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1040270","DOI":"10.3389\/fcimb.2022.1040270","article-title":"Pattern recognition receptor signaling and innate immune responses to schistosome infection","volume":"12","author":"Dibo","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"812774","DOI":"10.3389\/fimmu.2022.812774","article-title":"Toll-like receptor signaling and its role in cell-mediated immunity","volume":"13","author":"Duan","year":"2022","journal-title":"Front. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e57828","DOI":"10.15252\/embr.202357828","article-title":"USP3 plays a critical role in the induction of innate immune tolerance","volume":"24","author":"Duan","year":"2023","journal-title":"EMBO Rep."},{"key":"B23","doi-asserted-by":"publisher","first-page":"3733","DOI":"10.3390\/ijms23073733","article-title":"Necroptosis as a novel facet of mitotic catastrophe","volume":"23","author":"Egorshina","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1038\/cdd.2012.22","article-title":"dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8","volume":"19","author":"Estornes","year":"2012","journal-title":"Cell Death Differ."},{"key":"B25","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/ni921","article-title":"IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway","volume":"4","author":"Fitzgerald","year":"2003","journal-title":"Nat. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"C202","DOI":"10.1152\/ajpcell.00088.2022","article-title":"Proteoglycans in Toll-like receptor responses and innate immunity","volume":"323","author":"Garantziotis","year":"2022","journal-title":"Am. J. Physiology. Cell Physiology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"10923","DOI":"10.1073\/pnas.93.20.10923","article-title":"RIP and FADD: two \"death domain\"-containing proteins can induce apoptosis by convergent, but dissociable, pathways","volume":"93","author":"Grimm","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B28","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1128\/JVI.02008-08","article-title":"Activation of pattern recognition receptor-mediated innate immunity inhibits the replication of hepatitis B virus in human hepatocyte-derived cells","volume":"83","author":"Guo","year":"2009","journal-title":"J. Virol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"34474","DOI":"10.1074\/jbc.M112.401406","article-title":"Toll or interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-\u03b2 (TRIF)-mediated caspase-11 protease production integrates Toll-like receptor 4 (TLR4) protein- and Nlrp3 inflammasome-mediated host defense against enteropathogens","volume":"287","author":"Gurung","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nature04369","article-title":"Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6","volume":"439","author":"H\u00e4cker","year":"2006","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","first-page":"20054","DOI":"10.1073\/pnas.1116302108","article-title":"Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway","volume":"108","author":"He","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B32","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1038\/35037710","article-title":"The biochemistry of apoptosis","volume":"407","author":"Hengartner","year":"2000","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"10376","DOI":"10.1128\/jvi.79.16.10376-10385.2005","article-title":"Early alpha\/beta interferon production by myeloid dendritic cells in response to UV-inactivated virus requires viral entry and interferon regulatory factor 3 but not MyD88","volume":"79","author":"Hidmark","year":"2005","journal-title":"J. Virol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.immuni.2016.06.029","article-title":"The highway to hell: a RIP kinase-directed shortcut to inflammatory cytokine production","volume":"45","author":"Hildebrand","year":"2016","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1002\/hep.22470","article-title":"The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88","volume":"48","author":"Hritz","year":"2008","journal-title":"Hepatology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1093\/toxsci\/kfz193","article-title":"Liver inflammatory injury initiated by DAMPs-TLR4-MyD88\/TRIF-nf\u03bab signaling pathway is involved in monocrotaline-induced HSOS","volume":"172","author":"Huang","year":"2019","journal-title":"Toxicol. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/sj.emboj.7600991","article-title":"Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity","volume":"25","author":"Husebye","year":"2006","journal-title":"EMBO J."},{"key":"B38","doi-asserted-by":"publisher","first-page":"483","DOI":"10.4049\/jimmunol.180.1.483","article-title":"TLR3 increases disease morbidity and mortality from vaccinia infection","volume":"180","author":"Hutchens","year":"2008","journal-title":"J. Immunol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2467","DOI":"10.1007\/s10787-023-01327-5","article-title":"A low dose of naloxone mitigates autoimmune hepatitis by regulating TLR4\/NF-\u03baB and Nrf2\/HO-1 signaling pathways","volume":"31","author":"Ibrahim","year":"2023","journal-title":"Inflammopharmacology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.jhep.2009.03.027","article-title":"Contribution of TIR domain-containing adapter inducing IFN-beta-mediated IL-18 release to LPS-induced liver injury in mice","volume":"51","author":"Imamura","year":"2009","journal-title":"J. Hepatol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"3153","DOI":"10.4049\/jimmunol.178.5.3153","article-title":"Toll\/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-mediated signaling contributes to innate immune responses in the lung during Escherichia coli pneumonia","volume":"178","author":"Jeyaseelan","year":"2007","journal-title":"J. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"3878","DOI":"10.1038\/ncomms4878","article-title":"Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance","volume":"5","author":"Jia","year":"2014","journal-title":"Nat. Commun."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1007\/s13238-010-0141-8","article-title":"Mechanism of inhibiting type I interferon induction by hepatitis B virus X protein","volume":"1","author":"Jiang","year":"2010","journal-title":"Protein Cell"},{"key":"B44","doi-asserted-by":"publisher","first-page":"3533","DOI":"10.1073\/pnas.0308496101","article-title":"Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta","volume":"101","author":"Jiang","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B45","doi-asserted-by":"publisher","first-page":"16713","DOI":"10.1074\/jbc.M300562200","article-title":"Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)-independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR","volume":"278","author":"Jiang","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B46","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.cell.2006.03.047","article-title":"Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling","volume":"125","author":"Kagan","year":"2006","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/ni1569","article-title":"TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta","volume":"9","author":"Kagan","year":"2008","journal-title":"Nat. Immunol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"4942","DOI":"10.4049\/jimmunol.174.8.4942","article-title":"Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif","volume":"174","author":"Kaiser","year":"2005","journal-title":"J. Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"31268","DOI":"10.1074\/jbc.M113.462341","article-title":"Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL","volume":"288","author":"Kaiser","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/j.jaci.2006.02.023","article-title":"Toll-like receptor function and signaling","volume":"117","author":"Kaisho","year":"2006","journal-title":"J. Allergy Clin. Immunol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1038\/sj.cdd.4401051","article-title":"Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA","volume":"9","author":"Kalai","year":"2002","journal-title":"Cell Death Differ."},{"key":"B52","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1111\/j.1600-079X.2011.00858.x","article-title":"Melatonin protects liver against ischemia and reperfusion injury through inhibition of toll-like receptor signaling pathway","volume":"50","author":"Kang","year":"2011","journal-title":"J. Pineal Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1111\/j.1600-079X.2012.00972.x","article-title":"Melatonin inhibits type 1 interferon signaling of toll-like receptor 4 via heme oxygenase-1 induction in hepatic ischemia\/reperfusion","volume":"53","author":"Kang","year":"2012","journal-title":"J. Pineal Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e0112722","DOI":"10.1128\/msystems.01127-22","article-title":"A novel synbiotic alleviates autoimmune hepatitis by modulating the gut microbiota-liver Axis and inhibiting the hepatic TLR4\/NF-\u03baB\/NLRP3 signaling pathway","volume":"8","author":"Kang","year":"2023","journal-title":"mSystems"},{"key":"B55","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.1002\/jmv.24849","article-title":"Down regulation of TRIF, TLR3, and MAVS in HCV infected liver correlat es with the outcome of infection","volume":"89","author":"Kar","year":"2017","journal-title":"J. Med. virology"},{"key":"B56","doi-asserted-by":"publisher","first-page":"102172","DOI":"10.1016\/j.cbpa.2022.102172","article-title":"Toll-like receptor (TLR) agonists as a driving force behind next-generation vaccine adjuvants and cancer therapeutics","volume":"70","author":"Kaur","year":"2022","journal-title":"Curr. Opin. Chem. Biol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1038\/ni.1606","article-title":"Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2","volume":"9","author":"Kawagoe","year":"2008","journal-title":"Nat. Immunol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/ni.1863","article-title":"The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors","volume":"11","author":"Kawai","year":"2010","journal-title":"Nat. Immunol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"5887","DOI":"10.4049\/jimmunol.167.10.5887","article-title":"Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes","volume":"167","author":"Kawai","year":"2001","journal-title":"J. Immunol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"2130","DOI":"10.1038\/s41418-018-0098-3","article-title":"Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes","volume":"25","author":"Komine","year":"2018","journal-title":"Cell death Differ."},{"key":"B61","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.ijbiomac.2021.10.014","article-title":"The crosstalk between pattern-recognition receptor signaling and calcium signaling","volume":"192","author":"Kong","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1002\/jcb.30413","article-title":"An overview of programmed cell death: apoptosis and pyroptosis-Mechanisms, differences, and significance in organism physiology and pathophysiology","volume":"124","author":"Kowalski","year":"2023","journal-title":"J. Cell. Biochem."},{"key":"B63","doi-asserted-by":"publisher","first-page":"e53","DOI":"10.1371\/journal.ppat.0020053","article-title":"Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia","volume":"2","author":"Le Goffic","year":"2006","journal-title":"PLoS Pathog."},{"key":"B64","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1002\/hep.24763","article-title":"Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates","volume":"55","author":"Li","year":"2012","journal-title":"Hepatology"},{"key":"B65","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1038\/jid.2012.120","article-title":"Toll-like receptor 3 ligand polyinosinic:polycytidylic acid promotes wound healing in human and murine skin","volume":"132","author":"Lin","year":"2012","journal-title":"J. Investigative Dermatology"},{"key":"B66","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/nature09121","article-title":"Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR\/IL-1R signalling","volume":"465","author":"Lin","year":"2010","journal-title":"Nature"},{"key":"B67","doi-asserted-by":"publisher","first-page":"aaa2630","DOI":"10.1126\/science.aaa2630","article-title":"Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation","volume":"347","author":"Liu","year":"2015","journal-title":"Sci. (New York, N.Y.)"},{"key":"B68","doi-asserted-by":"publisher","first-page":"111084","DOI":"10.1016\/j.biopha.2020.111084","article-title":"Babao Dan improves neurocognitive function by inhibiting inflammation in clinical minimal hepatic encephalopathy","volume":"135","author":"Lu","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"B69","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1093\/cvr\/cvt033","article-title":"Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adapto rs in haematopoietic cells promotes atherosclerosis","volume":"99","author":"Lundberg","year":"2013","journal-title":"Cardiovasc Res."},{"key":"B70","doi-asserted-by":"publisher","first-page":"jcs239194","DOI":"10.1242\/jcs.239194","article-title":"Signalling, sorting and scaffolding adaptors for Toll-like receptors","volume":"133","author":"Luo","year":"2019","journal-title":"J. Cell Sci."},{"key":"B71","doi-asserted-by":"publisher","first-page":"105605","DOI":"10.1016\/j.fitote.2023.105605","article-title":"Hepatoprotective effect of total flavonoids from Carthamus tinctorius L. leaves against carbon tetrachloride-induced chronic liver injury in mice","volume":"171","author":"Ma","year":"2023","journal-title":"Fitoterapia"},{"key":"B72","doi-asserted-by":"publisher","first-page":"41827","DOI":"10.1074\/jbc.M510849200","article-title":"NF-kappaB protects macrophages from lipopolysaccharide-induced cell death: the role of caspase 8 and receptor-interacting protein","volume":"280","author":"Ma","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B73","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1038\/cmi.2017.43","article-title":"The IL-1R\/TLR signaling pathway is essential for efficient CD8+ T-cell responses against hepatitis B virus in the hydrodynamic injection mouse model","volume":"14","author":"Ma","year":"2017","journal-title":"Cell Mol. Immunol."},{"key":"B74","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.ejphar.2014.06.010","article-title":"Limonin attenuates hepatocellular injury following liver ischemia and reperfusion in rats via toll-like receptor dependent pathway","volume":"740","author":"Mahmoud","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1101\/sqb.1998.63.609","article-title":"Structure and function of the interferon-beta enhanceosome","volume":"63","author":"Maniatis","year":"1998","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/JLB.3MIR1218-483RR","article-title":"Below the surface: the inner lives of TLR4 and TLR9","volume":"106","author":"Marongiu","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"418","DOI":"10.4049\/jimmunol.1202756","article-title":"TLR3, TRIF, and caspase 8 determine double-stranded RNA-induced epithelial cell death and survival in vivo","volume":"190","author":"McAllister","year":"2013","journal-title":"J. Immunol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/35100529","article-title":"Toll-like receptors and innate immunity","volume":"1","author":"Medzhitov","year":"2001","journal-title":"Nat. Rev. Immunol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/ni1061","article-title":"RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation","volume":"5","author":"Meylan","year":"2004","journal-title":"Nat. Immunol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"5557","DOI":"10.1038\/s41598-020-61270-1","article-title":"New insights in acetaminophen toxicity: HMGB1 contributes by itself to amplify hepatocyte necrosis in vitro through the TLR4-TRIF-RIPK3 axis","volume":"10","author":"Minsart","year":"2020","journal-title":"Sci. Rep."},{"key":"B81","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1038\/s12276-022-00868-z","article-title":"Roles of RIPK3 in necroptosis, cell signaling, and disease","volume":"54","author":"Morgan","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"B82","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.immuni.2016.06.007","article-title":"RIPK1 and RIPK3 kinases promote cell-death-independent inflammation by toll-like receptor 4","volume":"45","author":"Najjar","year":"2016","journal-title":"Immunity"},{"key":"B83","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/ni886","article-title":"TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction","volume":"4","author":"Oshiumi","year":"2003","journal-title":"Nat. Immunol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1038\/nature07830","article-title":"The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex","volume":"458","author":"Park","year":"2009","journal-title":"Nature"},{"key":"B85","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1002\/hep.24059","article-title":"Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells","volume":"53","author":"Petrasek","year":"2011","journal-title":"Hepatology"},{"key":"B86","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/S2468-1253(22)00317-X","article-title":"Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis","volume":"8","author":"Quek","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1172\/JCI60893","article-title":"TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice","volume":"122","author":"Reinert","year":"2012","journal-title":"J. Clin. Investigation"},{"key":"B88","doi-asserted-by":"publisher","first-page":"2561","DOI":"10.4049\/jimmunol.1002029","article-title":"TRIF is a critical survival factor in viral cardiomyopathy","volume":"186","author":"Riad","year":"2011","journal-title":"J. Immunol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"79","author":"Rinella","year":"2023","journal-title":"J. Hepatol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"5805","DOI":"10.1007\/s12035-023-03433-5","article-title":"A review on caspases: key regulators of biological activities and apoptosis","volume":"60","author":"Sahoo","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"4894","DOI":"10.4049\/jimmunol.176.8.4894","article-title":"TLR3 can directly trigger apoptosis in human cancer cells","volume":"176","author":"Salaun","year":"2006","journal-title":"J. Immunol."},{"key":"B92","doi-asserted-by":"publisher","first-page":"4304","DOI":"10.4049\/jimmunol.171.8.4304","article-title":"Toll\/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling","volume":"171","author":"Sato","year":"2003","journal-title":"J. Immunol."},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.MCHD-0040-2016","article-title":"Toll-like receptor signaling and its inducible proteins","volume":"4","author":"Satoh","year":"2016","journal-title":"Microbiol. Spectr."},{"key":"B94","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/s0002-9440(10)61693-8","article-title":"Mechanisms of beta-cell death in response to double-stranded (ds) RNA and interferon-gamma: dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent necrosis","volume":"159","author":"Scarim","year":"2001","journal-title":"Am. J. Pathology"},{"key":"B95","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1038\/nm1663","article-title":"TLR4 enhances TGF-beta signaling and hepatic fibrosis","volume":"13","author":"Seki","year":"2007","journal-title":"Nat. Med."},{"key":"B96","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1101\/gad.312561.118","article-title":"Necroptosis in development and diseases","volume":"32","author":"Shan","year":"2018","journal-title":"Genes Dev."},{"key":"B97","doi-asserted-by":"publisher","first-page":"109450","DOI":"10.1016\/j.jnutbio.2023.109450","article-title":"Vitamin D deficiency exacerbates alcohol-related liver injury via gut barrier disruption and hepatic overload of endotoxin","volume":"122","author":"Shibamoto","year":"2023","journal-title":"J. Nutr. Biochem."},{"key":"B98","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1089\/jir.2014.0096","article-title":"Interferon-\u03b2 mediates signaling pathways uniquely regulated in hepatic stellate cells and attenuates the progression of hepatic fibrosis in a dietary mouse model","volume":"35","author":"Shimozono","year":"2015","journal-title":"J. Interferon Cytokine Res."},{"key":"B99","doi-asserted-by":"publisher","first-page":"437","DOI":"10.4161\/gmic.20873","article-title":"TRIF mobilizes unique primary defense against Gram-negative bacteria in intestinal interface","volume":"3","author":"Sotolongo","year":"2012","journal-title":"Gut Microbes"},{"key":"B100","doi-asserted-by":"publisher","first-page":"9505","DOI":"10.1074\/jbc.M109488200","article-title":"Identification of a novel homotypic interaction motif required for the phosphorylation of receptor-interacting protein (RIP) by RIP3","volume":"277","author":"Sun","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B101","doi-asserted-by":"publisher","first-page":"10186","DOI":"10.1074\/jbc.M117.796631","article-title":"Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1-IKK\u03f5-IRF3 axis activation","volume":"293","author":"Tsukamoto","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B102","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1189\/jlb.2RI1115-531R","article-title":"TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target","volume":"100","author":"Ullah","year":"2016","journal-title":"J. Leukoc. Biol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1111\/imm.13664","article-title":"TLR3\/TRIF pathway confers protection against herpes simplex encephalit is through NK cell activation mediated by a loop of type I IFN and IL- 15 from epithelial and dendritic cells","volume":"170","author":"Uyangaa","year":"2023","journal-title":"Immunology"},{"key":"B104","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1038\/nrm2970","article-title":"Molecular mechanisms of necroptosis: an ordered cellular explosion","volume":"11","author":"Vandenabeele","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1007\/s12072-023-10568-z","article-title":"Current understanding and future perspectives on the impact of changing NAFLD to MAFLD on global epidemiology and clinical outcomes","volume":"17","author":"Vaz","year":"2023","journal-title":"Hepatol. Int."},{"key":"B106","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.2174\/138945012803530260","article-title":"Adaptors in toll-like receptor signaling and their potential as therapeutic targets","volume":"13","author":"Ve","year":"2012","journal-title":"Curr. Drug Targets"},{"key":"B107","doi-asserted-by":"publisher","first-page":"13507","DOI":"10.1073\/pnas.1714386114","article-title":"Crystal structure of human IRAK1","volume":"114","author":"Wang","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B108","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1038\/ncb1996","article-title":"Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling","volume":"11","author":"Woo","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"B109","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/ncb2408","article-title":"Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B","volume":"14","author":"Woo","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"B110","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1038\/cdd.2014.77","article-title":"Distinct roles of RIP1-RIP3 hetero- and RIP3-RIP3 homo-interaction in mediating necroptosis","volume":"21","author":"Wu","year":"2014","journal-title":"Cell Death Differ."},{"key":"B111","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.yexcr.2015.07.007","article-title":"Long-term use of indomethacin leads to poor prognoses through promoting the expression of PD-1 and PD-L2 via TRIF\/NF-\u03baB pathway and JAK\/STAT3 pathway to inhibit TNF-\u03b1 and IFN-\u03b3 in hepatocellular carcinoma","volume":"337","author":"Xu","year":"2015","journal-title":"Exp. Cell Res."},{"key":"B112","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s13045-021-01191-2","article-title":"Toll-like receptors and toll-like receptor-targeted immunotherapy against glioma","volume":"14","author":"Xun","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"B113","doi-asserted-by":"publisher","first-page":"7825","DOI":"10.1007\/s11033-023-08438-w","article-title":"Emerging trends in IRAK-4 kinase research","volume":"50","author":"Yadav","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"B114","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1126\/science.1087262","article-title":"Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway","volume":"301","author":"Yamamoto","year":"2003","journal-title":"Science"},{"key":"B115","doi-asserted-by":"publisher","first-page":"6668","DOI":"10.4049\/jimmunol.169.12.6668","article-title":"Cutting edge: a novel Toll\/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling","volume":"169","author":"Yamamoto","year":"2002","journal-title":"J. Immunol."},{"key":"B116","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.jcmgh.2016.12.004","article-title":"TRIF differentially regulates hepatic steatosis and inflammation\/fibrosis in mice","volume":"3","author":"Yang","year":"2017","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"B117","doi-asserted-by":"publisher","first-page":"1049340","DOI":"10.3389\/fimmu.2022.1049340","article-title":"Toll-like receptor-targeted anti-tumor therapies: advances and challenges","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Immunol."},{"key":"B118","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.4049\/jimmunol.178.4.2204","article-title":"Suppression of the effector phase of inflammatory arthritis by double-stranded RNA is mediated by type I IFNs","volume":"178","author":"Yarilina","year":"2007","journal-title":"J. Immunol."},{"key":"B119","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"B120","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.4049\/jimmunol.1001499","article-title":"Double-stranded RNA induces shedding of the 34-kDa soluble TNFR1 from human airway epithelial cells via TLR3-TRIF-RIP1-dependent signaling: roles for dual oxidase 2- and caspase-dependent pathways","volume":"186","author":"Yu","year":"2011","journal-title":"J. Immunol."},{"key":"B121","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1089\/vim.2014.0039","article-title":"Toll-like receptor 4 and hepatitis B infection: molecular mechanisms and pathogenesis","volume":"27","author":"Zare-Bidaki","year":"2014","journal-title":"Viral Immunol."},{"key":"B122","doi-asserted-by":"publisher","first-page":"7115","DOI":"10.4049\/jimmunol.173.12.7115","article-title":"Cutting edge: TLR4 activation mediates liver ischemia\/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway","volume":"173","author":"Zhai","year":"2004","journal-title":"J. Immunol."},{"key":"B123","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1126\/science.1172308","article-title":"RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis","volume":"325","author":"Zhang","year":"2009","journal-title":"Sci. (New York, N.Y.)"},{"key":"B124","doi-asserted-by":"publisher","first-page":"676946","DOI":"10.3389\/fimmu.2021.676946","article-title":"RIPK1-Associated inborn errors of innate immunity","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Immunol."},{"key":"B125","doi-asserted-by":"publisher","first-page":"3049","DOI":"10.4049\/jimmunol.181.5.3049","article-title":"TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol","volume":"181","author":"Zhao","year":"2008","journal-title":"J. Immunol."},{"key":"B126","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/s41586-018-0372-z","article-title":"New mitochondrial DNA synthesis enables NLRP3 inflammasome activation","volume":"560","author":"Zhong","year":"2018","journal-title":"Nature"},{"key":"B127","doi-asserted-by":"publisher","first-page":"28713","DOI":"10.3402\/jev.v4.28713","article-title":"Ginger-derived nanoparticles protect against alcohol-induced liver damage","volume":"4","author":"Zhuang","year":"2015","journal-title":"J. Extracell. Vesicles"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2024.1370042\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T04:54:40Z","timestamp":1713329680000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2024.1370042\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,17]]},"references-count":127,"alternative-id":["10.3389\/fcell.2024.1370042"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2024.1370042","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,17]]},"article-number":"1370042"}}