p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice
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
Affiliations
Young-Su Yi
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA; Department of Pharmaceutical Engineering, Cheongju University, Cheongju 28503, Republic of Korea
Jinlong Jian
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA
Elena Gonzalez-Gugel
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA
Yong-Xiang Shi
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA; Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, China
Qingyun Tian
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA
Wenyu Fu
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA
Aubryanna Hettinghouse
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA
Wenhao Song
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA
Ronghan Liu
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA
Michun He
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA
Huabing Qi
Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair (CBMR),Trauma Center, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Third Military Medical University, China
Jing Yang
Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair (CBMR),Trauma Center, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Third Military Medical University, China
Xiaolan Du
Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair (CBMR),Trauma Center, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Third Military Medical University, China
GuoZhi Xiao
Department of Biology and Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen 518055, China; Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA
Lin Chen
Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair (CBMR),Trauma Center, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Third Military Medical University, China; Correspondence to: L. Chen, Center of Bone Metabolism and Repair, Trauma Center, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Chuan-ju Liu
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA; Correspondence to: C-J. Liu, Rm 1608, HJD, New York University School of Medicine, 301 East 17th Street, New York, NY 10003, USA.
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
