title: Enhanced TLR-induced NF-κB signaling and type I interferon responses in NLRC5 deficient mice.
abstract: Nod-like receptors (NLRs) are intracellular sensors that respond to a variety of pathogen and intracellular danger signals to induce innate immune responses. NLRC5 has recently been identified to be an important regulator of NF-κB, type I interferon (IFN) and inflammasome signaling pathways, but the in vivo function and mechanisms of NLRC5 remain to be defined. Here, we describe the generation and characterization of NLRC5 knockout mice. We show that induction of NLRC5 expression by Toll-like receptor (TLR) ligand or cytokine stimulation requires the signal transducers and activators of transcription (Stat)1-mediated signaling pathway. NLRC5 ablation reduces MHC class I expression, and enhances IKK and IRF3 phosphorylation in response to TLR stimulation or viral infection. Consistent with these observations, we found that NLRC5 deficiency enhanced IL-6 and IFN-β production in mouse embryonic fibroblasts (MEFs), peritoneal macrophages and bone marrow-derived macrophages (BMMs), but not bone marrow-derived dendritic cells (BMDCs) after LPS stimulation or vesicular stomatitis virus (VSV) infection. Furthermore, we found that NLRC5-deficient mice produced higher amounts of IL-6 and IFN-β in the sera when they were challenged with LPS or infected with VSV. Taken together, these results provide in vivo evidence that NLRC5 plays critical roles in MHC class I expression, innate immune signaling and antiviral innate immune responses, thus serving as an important target for modulating innate immune signaling and regulation.
authors.affiliation: The Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yanzheng
authors.initials: Y
authors.lastname: Tong
authors.forename: Jun
authors.initials: J
authors.lastname: Cui
authors.forename: Qingtian
authors.initials: Q
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Zou
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Wang
authors.forename: Rong-Fu
authors.initials: RF
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D018116:Vesiculovirus / Q000472:pathogenicity
chemical_list: D015395:Histocompatibility Antigens Class I; D058847:Inflammasomes; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C494233:Irf3 protein, mouse; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; C549161:NLRC5 protein, mouse; D050791:STAT Transcription Factors; D051193:Toll-Like Receptors; D051550:I-kappa B Kinase