TRIF-dependent Signaling and Its Role in Liver Diseases

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2024 May 2

PMID 38694821

Authors

Lilin Hu

Zilu Cheng

Huikuan Chu

Weijun Wang

Yu Jin

Ling Yang

Affiliations

Soon will be listed here.

Abstract

TIR domain-containing adaptor inducing IFN-β (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-β) response, nuclear factor kappa B (NF-κB) 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's 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.

References

Cai S, Batra S, Shen L, Wakamatsu N, Jeyaseelan S . Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection. J Immunol. 2009; 183(10):6629-38. PMC: 2777750. DOI: 10.4049/jimmunol.0901033. View

Zhai Y, Shen X, OConnell R, Gao F, Lassman C, Busuttil R . Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol. 2004; 173(12):7115-9. DOI: 10.4049/jimmunol.173.12.7115. View

Gurung P, Malireddi R, Anand P, Demon D, Vande Walle L, Liu Z . Toll or interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF)-mediated caspase-11 protease production integrates Toll-like receptor 4 (TLR4) protein- and Nlrp3 inflammasome-mediated host defense against enteropathogens. J Biol Chem. 2012; 287(41):34474-83. PMC: 3464552. DOI: 10.1074/jbc.M112.401406. View

Hildebrand J, Murphy J . The Highway to Hell: A RIP Kinase-Directed Shortcut to Inflammatory Cytokine Production. Immunity. 2016; 45(1):1-3. DOI: 10.1016/j.immuni.2016.06.029. View

Rinella M, Lazarus J, Ratziu V, Francque S, Sanyal A, Kanwal F . A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023; 79(6):1542-1556. DOI: 10.1016/j.jhep.2023.06.003. View

Ullah M, Sweet M, Mansell A, Kellie S, Kobe B . TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target. J Leukoc Biol. 2016; 100(1):27-45. DOI: 10.1189/jlb.2RI1115-531R. View

Grimm S, Stanger B, Leder P . RIP and FADD: two "death domain"-containing proteins can induce apoptosis by convergent, but dissociable, pathways. Proc Natl Acad Sci U S A. 1996; 93(20):10923-7. PMC: 38259. DOI: 10.1073/pnas.93.20.10923. View

Colasanti O, Burm R, Huang H, Riedl T, Traut J, Gillich N . Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation. J Hepatol. 2023; 79(3):645-656. DOI: 10.1016/j.jhep.2023.04.023. View

Husebye H, Halaas O, Stenmark H, Tunheim G, Sandanger O, Bogen B . Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity. EMBO J. 2006; 25(4):683-92. PMC: 1383569. DOI: 10.1038/sj.emboj.7600991. View

10.

Lin Q, Wang L, Lin Y, Liu X, Ren X, Wen S . Toll-like receptor 3 ligand polyinosinic:polycytidylic acid promotes wound healing in human and murine skin. J Invest Dermatol. 2012; 132(8):2085-92. DOI: 10.1038/jid.2012.120. View

11.

Kang J, Lee S . Melatonin inhibits type 1 interferon signaling of toll-like receptor 4 via heme oxygenase-1 induction in hepatic ischemia/reperfusion. J Pineal Res. 2012; 53(1):67-76. DOI: 10.1111/j.1600-079X.2012.00972.x. View

12.

Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y . Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol. 2008; 9(6):684-91. DOI: 10.1038/ni.1606. View

13.

Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin X . New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018; 560(7717):198-203. PMC: 6329306. DOI: 10.1038/s41586-018-0372-z. View

14.

Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M . RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol. 2004; 5(5):503-7. DOI: 10.1038/ni1061. View

15.

Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H . Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003; 301(5633):640-3. DOI: 10.1126/science.1087262. View

16.

Ayoobi F, Hassanshahi G, Zainodini N, Khorramdelazad H, Arababadi M, Kennedy D . Reduced expression of TRIF in chronic HBV infected Iranian patients. Clin Res Hepatol Gastroenterol. 2013; 37(5):491-5. DOI: 10.1016/j.clinre.2012.11.005. View

17.

Duan T, Feng Y, Du Y, Xing C, Chu J, Ou J . USP3 plays a critical role in the induction of innate immune tolerance. EMBO Rep. 2023; 24(12):e57828. PMC: 10702844. DOI: 10.15252/embr.202357828. View

18.

Shan B, Pan H, Najafov A, Yuan J . Necroptosis in development and diseases. Genes Dev. 2018; 32(5-6):327-340. PMC: 5900707. DOI: 10.1101/gad.312561.118. View

19.

Zhang J, Jin T, Aksentijevich I, Zhou Q . RIPK1-Associated Inborn Errors of Innate Immunity. Front Immunol. 2021; 12:676946. PMC: 8215710. DOI: 10.3389/fimmu.2021.676946. View

20.

Xu P, Sun Z, Wang Y, Miao C . Long-term use of indomethacin leads to poor prognoses through promoting the expression of PD-1 and PD-L2 via TRIF/NF-κB pathway and JAK/STAT3 pathway to inhibit TNF-α and IFN-γ in hepatocellular carcinoma. Exp Cell Res. 2015; 337(1):53-60. DOI: 10.1016/j.yexcr.2015.07.007. View