RasGRP3 Limits Toll-like Receptor-triggered Inflammatory Response in Macrophages by Activating Rap1 Small GTPase

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Aug 15

PMID 25118589

Citations 26

Authors

Songqing Tang

Taoyong Chen

Zhou Yu

Xuhui Zhu

Mingjin Yang

Bin Xie

Nan Li

Xuetao Cao

Jianli Wang

Affiliations

Soon will be listed here.

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.

Citing Articles

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