title: Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation.
abstract: Single Ig IL-1R-related molecule (SIGIRR, also called IL-1R8 or Toll/IL-1R [TIR]8), a negative regulator for Toll/IL-1R signaling, plays critical roles in innate immunity and various diseases in mammals. However, the occurrence of this molecule in ancient vertebrates and its function in liver homeostasis and disorders remain poorly understood. In this study, we identified a SIGIRR homology from zebrafish (Danio rerio [DrSIGIRR]) by using a number of conserved structural and functional hallmarks to its mammalian counterparts. DrSIGIRR was highly expressed in the liver. Ablation of DrSIGIRR by lentivirus-delivered small interfering RNA in the liver significantly enhanced hepatic inflammation in response to polyinosinic-polycytidylic acid [poly(I:C)] stimulation, as shown by the upregulation of inflammatory cytokines and increased histological disorders. In contrast, depletion of TIR domain-containing adaptor inducing IFN-β (TRIF) or administration of TRIF signaling inhibitor extremely abrogated the poly(I:C)-induced hepatic inflammation. Aided by the zebrafish embryo model, overexpression of DrSIGIRR in vivo significantly inhibited the poly(I:C)- and TRIF-induced NF-κB activations; however, knockdown of DrSIGIRR promoted such activations. Furthermore, pull-down and Duolink in situ proximity ligation assay assays showed that DrSIGIRR can interact with the TRIF protein. Results suggest that DrSIGIRR plays an inhibitory role in TRIF-mediated inflammatory reactions by competitive recruitment of the TRIF adaptor protein from its TLR3/TLR22 receptor. To our knowledge, this study is the first to report a functional SIGIRR homolog that existed in a lower vertebrate. This molecule is essential to establish liver homeostasis under inflammatory stimuli. Overall, the results will enrich the current knowledge about SIGIRR-mediated immunity and disorders in the liver.
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Gu
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and.
authors.forename: Li
authors.initials: L
authors.lastname: Nie
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and.
authors.forename: Dong-Yang
authors.initials: DY
authors.lastname: Guo
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and shaojz@zju.edu.cn xianglx@zju.edu.cn.
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Xiang
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, People's Republic of China; and Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266200, People's Republic of China shaojz@zju.edu.cn xianglx@zju.edu.cn.
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Shao
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D029941:Fish Proteins / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008322:Mammals; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D015027:Zebrafish / Q000276:immunology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D029941:Fish Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D011070:Poly I-C; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; D051196:Toll-Like Receptor 3; D029961:Zebrafish Proteins; C000621722:SIGIRR protein, zebrafish; C520367:TICAM1 protein, zebrafish; C546891:SIGIRR protein, human