NLRC5 Limits the Activation of Inflammatory Pathways
NLRC5 Limits the Activation of Inflammatory Pathways
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DOI：
10.4049/jimmunol.0903900
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发表时间：
2010-08-01
影响因子：
4.4
通讯作者：
Girardin, Stephen E.
中科院分区：
文献类型：
--
作者：
Benko, Szilvia;Magalhaes, Joao G.;Girardin, Stephen E.
nod样受体（NLRs）是细胞内哨兵蛋白，参与微生物和危险信号的检测，从而控制几个关键的先天免疫途径。人类基因组编码22种NLR蛋白，其中许多蛋白的功能尚不清楚。在这项研究中，我们提出了NLRC5的鉴定和表征，NLRC5是一种主要在髓系和淋巴系细胞中表达的NLR蛋白。ifn - γ强烈诱导NLRC5表达，LPS和多肌苷（polyinosic: polycytidyacid）诱导NLRC5表达较弱。NLRC5在HEK293T细胞中的过表达导致nf - κ B-、AP-1-和I型ifn依赖性信号的全局抑制，这很可能是通过转录抑制实现的。因此，NLRC5被发现以依赖于crma的方式在细胞质和细胞核之间穿梭。在RAW264.7小鼠巨噬细胞中敲低NLRC5的表达可导致ifn - γ和LPS的促炎反应显著上调，包括TNF、IL-6和IL-1 β的分泌增加，以及细胞表面CD40的表达增加。引人注目的是，NLRC5的表达也被发现对lps诱导的RAW264.7巨噬细胞中IL-10的产生至关重要。总之，我们的研究结果确定NLRC5是炎症通路的负调节因子。中华免疫学杂志，2010,18(5):1681-1691。
Nod-like receptors (NLRs) are intracellular sentinel proteins that are implicated in the detection of microbes and danger signals, thereby controlling several key innate immune pathways. The human genome encodes 22 NLR proteins, the function of many of which remains unknown. In this study, we present the identification and characterization of NLRC5, a NLR protein whose expression is found predominantly in cells of the myeloid and lymphoid lineages. NLRC5 expression was strongly induced by IFN-gamma and more modestly by LPS and polyinosinic: polycytidylic acid. Overexpression of NLRC5 in HEK293T cells resulted in a global dampening of NF-kappa B-, AP-1-, and type I IFN-dependent signaling, most likely through transcriptional repression. Accordingly, NLRC5 was found to shuttle between the cytosol and the nucleus in a CrmA-dependent manner. Knocking down NLRC5 expression in RAW264.7 murine macrophages resulted in a potent upregulation of the proinflammatory responses to IFN-gamma and LPS, including increased secretion of TNF, IL-6, and IL-1 beta, as well as cell surface expression of CD40. Strikingly, NLRC5 expression was also found to be critical for LPS-induced IL-10 production in RAW264.7 macrophages. Collectively, our results identify NLRC5 as a negative modulator of inflammatory pathways. The Journal of Immunology, 2010, 185: 1681-1691.