p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice

• Main Authors: Young-Su Yi, Jinlong Jian, Elena Gonzalez-Gugel, Yong-Xiang Shi, Qingyun Tian, Wenyu Fu, Aubryanna Hettinghouse, Wenhao Song, Ronghan Liu, Michun He, Huabing Qi, Jing Yang, Xiaolan Du, GuoZhi Xiao, Lin Chen, Chuan-ju Liu
• Format: Article
• Language: English
• Published: Elsevier 2018-03-01
• Series: EBioMedicine
• Online Access: http://www.sciencedirect.com/science/article/pii/S2352396418300665

p204, a murine member of an interferon-inducible p200 family, was reported to recognize intracellular viral and bacterial DNAs, however, its role in the innate immunity in vivo remains unknown due to the lack of p204-deficient animal models. In this study we first generated the p204−/− mice. Unexpectedly, p204 deficiency led to significant defect in extracellular LPS signaling in macrophages, as demonstrated by dramatic reductions of LPS-mediated IFN-β and pro-inflammatory cytokines. The serum levels of IFN-β and pro-inflammatory cytokines were also significantly reduced in p204−/− mice following LPS challenge. In addition, p204−/− mice were resistant to LPS-induced shock. LPS-activated NF-ĸB and IRF-3 pathways were all defective in p204-deficient macrophages. p204 binds to TLR4 through its Pyrin domain, and it is required for the dimerization of TLR4 following LPS-challenge. Collectively, p204 is a critical component of canonical LPS-TLR4 signaling pathway, and these studies also suggest that p204 could be a potential target to prevent and treat inflammatory and infectious diseases. Keywords: p204, LPS, TLR4, IFN-β, Inflammatory responses, Macrophages