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 and Jianli Wang ()
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Songqing Tang: Institute of Immunology, Zhejiang University School of Medicine
Taoyong Chen: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University
Zhou Yu: Institute of Immunology, Zhejiang University School of Medicine
Xuhui Zhu: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University
Mingjin Yang: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University
Bin Xie: Institute of Immunology, Zhejiang University School of Medicine
Nan Li: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University
Xuetao Cao: Institute of Immunology, Zhejiang University School of Medicine
Jianli Wang: Institute of Immunology, Zhejiang University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms5657

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