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.
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 10003, USA.
EBioMedicine. 2018 Mar;29:78-91. doi: 10.1016/j.ebiom.2018.02.012. Epub 2018 Feb 16.
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.
p204 是干扰素诱导的 p200 家族中的一种鼠类蛋白，据报道其可识别细胞内的病毒和细菌 DNA，然而由于缺乏 p204 缺陷型动物模型，其在体内固有免疫中的作用尚不清楚。在本研究中，我们首先构建了 p204 敲除小鼠。出乎意料的是，p204 缺陷导致巨噬细胞中细胞外 LPS 信号显著受损，表现在 LPS 介导的 IFN-β 和促炎细胞因子的产生显著减少。LPS 攻击后，p204 敲除小鼠的血清 IFN-β 和促炎细胞因子水平也显著降低。此外，p204 敲除小鼠对 LPS 诱导的休克具有抗性。LPS 激活的 NF-κB 和 IRF-3 通路在 p204 缺陷型巨噬细胞中均存在缺陷。p204 通过其 Pyrin 结构域与 TLR4 结合，并且是 LPS 刺激后 TLR4 二聚化所必需的。总之，p204 是经典 LPS-TLR4 信号通路的关键组成部分，这些研究还表明 p204 可能是预防和治疗炎症和感染性疾病的潜在靶点。
