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Nat Com:鸟苷酸交换因子抑制巨噬细胞炎症反应的机制

摘要 : 浙江大学医学院和第二军医大学的研究人员在新研究中证实,遭受低强度的病原体感染时,鸟苷酸交换因子RasGRP3通过激活Rap1的小GTP酶限制Toll样受体触发的巨噬细胞的炎症反应。相关文章发表于2014年8月14日的《Nature Communications》杂志上。
图示:RasGRP3抑制DSS诱导的结肠炎的炎症。

图示:RasGRP3抑制DSS诱导的结肠炎的炎症。

浙江大学医学院的王建莉(Jianli Wang)教授和第二军医大学的陈涛勇(Taoyong Chen)教授领导的研究组在这项研究中,证实鸟苷酸交换因子RasGRP3通过检测到极低水平的Toll 样受体(TLR)配体,激活模式识别受体1(Rap1),限制了巨噬细胞中生成促炎细胞因子,尤其是IL-6。

他们发现在巨噬细胞中RasGRP3可破坏TLR3/4/9诱导IL-6生成,减轻葡聚糖硫酸钠(dextran sulphate sodium,DSS)诱导的结肠炎和胶原诱发性关节炎。在通过CRISPR-Cas9基因组编辑获得的RasGRP3缺陷RAW264.7细胞中,研究人员证实TLR3/4/9诱导Rap1激活受到抑制,而ERK1/2激活增高。

新研究证实在遭受低强度的病原体感染时RasGRP3通过激活Rap1限制了炎症反应,从而为防止过度的炎症反应设置了阈值。

原文摘要:

​RasGRP3 limits Toll-like receptor-triggered inflammatory response in macrophages by activating ​Rap1 small GTPase

Songqing Tang, Taoyong Chen, Zhou Yu, Xuhui Zhu, Mingjin Yang, Bin Xie, Nan Li, Xuetao Cao & Jianli Wang

Host immune cells can detect and destruct invading pathogens via pattern-recognition receptors. Small Rap GTPases act as conserved molecular switches coupling extracellular signals to various cellular responses, but their roles as regulators in Toll-like receptor (TLR) signalling have not been fully elucidated. Here we report that ​Ras guanine nucleotide-releasing protein 3 (​RasGRP3), a guanine nucleotide-exchange factor activating Ras and ​Rap1, limits production of proinflammatory cytokines (especially ​IL-6) in macrophages by activating ​Rap1 on activation by low levels of TLR agonists. We demonstrate that ​RasGRP3, a dominant member of RasGRPs in macrophages, impairs ​TLR3/4/9-induced ​IL-6 production and relieves dextrane sulphate sodium-induced colitis and collagen-induced arthritis. In ​RasGRP3-deficient RAW264.7 cells obtained by CRISPR-​Cas9genome editing, ​TLR3/4/9-induced activation of ​Rap1 was inhibited while ​ERK1/2 activation was enhanced. Our study suggests that ​RasGRP3 limits inflammatory response by activating ​Rap1 on low-intensity pathogen infection, setting a threshold for preventing excessive inflammatory response.

来源: Nature 浏览次数:83

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