Enhanced TLR-induced NF-κB signaling and type I interferon responses in NLRC5 deficient mice

Yanzheng Tong, Jun Cui, Qingtian Li, Jia Zou, Helen Y. Wang, Rong Fu Wang

Research output: Contribution to journalArticle

68 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)822-835
Number of pages14
JournalCell Research
Volume22
Issue number5
DOIs
StatePublished - May 2012

Keywords

  • innate immune signaling
  • NF-κB activation
  • Nod-like receptors
  • type I interferon signaling

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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