RasGRP3 limits Toll-like receptor-triggered inflammatory response in macrophages by activating Rap1 small GTPase.
RasGRP3 limits Toll-like receptor-triggered inflammatory response in macrophages by activating Rap1 small GTPase.
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RasGRP3 通过激活 Rap1 小 GTPase 限制巨噬细胞中 Toll 样受体触发的炎症反应
DOI：
10.1038/ncomms5657
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发表时间：
2014-08-14
影响因子：
16.6
通讯作者：
Wang, Jianli
中科院分区：
文献类型：
--
作者：
Tang, Songqing;Chen, Taoyong;Yu, Zhou;Zhu, Xuhui;Yang, Mingjin;Xie, Bin;Li, Nan;Cao, Xuetao;Wang, Jianli
宿主免疫细胞可以通过模式识别受体检测和破坏入侵的病原体。小Rap GTP酶作为保守的分子开关，将细胞外信号与各种细胞反应偶联，但它们作为Toll样受体（TLR）信号传导的调节剂的作用尚未完全阐明。在这里，我们报告，Ras鸟嘌呤核苷酸释放蛋白3（RasGRP 3），鸟嘌呤核苷酸交换因子激活Ras和Rap 1，限制生产的促炎细胞因子（特别是IL-6）在巨噬细胞中激活Rap 1激活低水平的TLR激动剂。我们证明，RasGRP 3，在巨噬细胞中的RasGRPs的主要成员，损害TLR 3/4/9诱导的IL-6的产生和减轻葡聚糖硫酸钠诱导的结肠炎和胶原诱导的关节炎。在通过CRISPR-Cas9基因组编辑获得的RasGRP 3缺陷型RAW264.7细胞中，TLR 3/4/9诱导的Rap 1活化被抑制，而ERK 1/2活化被增强。我们的研究表明，RasGRP 3通过在低强度病原体感染时激活Rap 1来限制炎症反应，为防止过度的炎症反应设定阈值。 Toll样受体（TLR）将微生物感测与免疫应答的启动偶联，其对于防御病原体是必不可少的，但当过度激活时可能导致免疫病理学。在这里，作者表明RasGRP 3设定了TLR激活的阈值，以防止免疫病理学。
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-Cas9 genome 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. Toll like receptors (TLRs) couple microbial sensing to initiation of immune responses, which are essential for defense against pathogens but may cause immunopathology when activated excessively. Here the authors show that RasGRP3 sets a threshold of TLR activation to prevent immunopathology.
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DOI：
10.4049/jimmunol.181.8.5501
发表时间：
2008-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chung J;Serezani CH;Huang SK;Stern JN;Keskin DB;Jagirdar R;Brock TG;Aronoff DM;Peters-Golden M
通讯作者：
Peters-Golden M
影响因子：
30.5
作者：
Katagiri, Koko;Imamura, Masashi;Kinashi, Tatsuo
通讯作者：
Kinashi, Tatsuo
影响因子：
30.5
作者：
Arbibe, L;Mira, JP;Knaus, UG
通讯作者：
Knaus, UG
影响因子：
5.3
作者：
Duchniewicz, M;Zemojtel, T;Zwartkiruis, FJT
通讯作者：
Zwartkiruis, FJT
影响因子：
4.8
作者：
Clyde-Smith, J;Silins, G;Hancock, JF
通讯作者：
Hancock, JF