GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages

doi:10.1038/s41401-021-00825-y

	GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages
	Zhang, Qing 1,2; Chen, Lin-hai 1; Yang, Hui 1; Fang, You-chen 1; Wang, Si-wei 1,3; Wang, Min 1; Yuan, Qian-ting 1; Wu, Wei 4; Zhang, Yang-ming 5; Liu, Zhan-ju 4
刊名	ACTA PHARMACOLOGICA SINICA
	2021-12-15
页码	13
关键词	GPR84 medium chain fatty acid receptor GPCR inflammatory bowel diseases ulcerative colitis NLRP3 inflammasome macrophages
ISSN号	1671-4083
DOI	10.1038/s41401-021-00825-y
通讯作者	Liu, Zhan-ju(liuzhanju88@126.com) ; Nan, Fa-jun(fjnan@simm.ac.cn) ; Xie, Xin(xxie@simm.ac.cn)
英文摘要	The putative medium-chain free fatty acid receptor GPR84 is a G protein-coupled receptor primarily expressed in myeloid cells that constitute the innate immune system, including neutrophils, monocytes, and macrophages in the periphery and microglia in the brain. The fact that GPR84 expression in leukocytes is remarkably increased under acute inflammatory stimuli such as lipopolysaccharide (LPS) and TNF alpha suggests that it may play a role in the development of inflammatory and fibrotic diseases. Here we demonstrate that GPR84 is highly upregulated in inflamed colon tissues of active ulcerative colitis (UC) patients and dextran sulfate sodium (DSS)-induced colitis mice. Infiltrating GPR84(+) macrophages are significantly increased in the colonic mucosa of both the UC patients and the mice with colitis. Consistently, GPR84(-/-) mice are resistant to the development of colitis induced by DSS. GPR84 activation imposes pro-inflammatory properties in colonic macrophages through enhancing NLRP3 inflammasome activation, while the loss of GPR84 prevents the M1 polarization and properties of proinflammatory macrophages. CLH536, a novel GPR84 antagonist discovered by us, suppresses colitis by reducing the polarization and function of pro-inflammatory macrophages. These results define a unique role of GPR84 in innate immune cells and intestinal inflammation, and suggest that GPR84 may serve as a potential drug target for the treatment of UC. GPR84 is positively correlated with ulcerative colitis in patients. Deletion or blockade of GPR84 alleviates colitis in mice via reducing NLRP3 activation and M1 polarization
资助项目	National Natural Science Foundation of China[81730099] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[22077132] ; Shanghai Science and Technology Commission[20S11903200] ; Shanghai Science and Technology Commission[20ZR1471200] ; Shanghai Science and Technology Commission[19ZR1411600] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020229] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-002] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2020283] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2017329]
WOS关键词	CHAIN FATTY-ACIDS ; PROTEIN-COUPLED RECEPTORS ; EXPERIMENTAL COLITIS ; MASTER REGULATORS ; SENSING RECEPTOR ; CROHNS-DISEASE ; BOWEL-DISEASE ; IMMUNE CELLS ; GUT ; PATHOGENESIS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBL GROUP
WOS记录号	WOS:000730502300002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/299169]
专题	中国科学院上海药物研究所
通讯作者	Liu, Zhan-ju; Nan, Fa-jun; Xie, Xin
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Peoples Hosp 10, Dept Gastroenterol, Shanghai 200072, Peoples R China 5.Burgeon Therapeut Co Ltd, Shanghai 201203, Peoples R China 6.Yantai Inst Mat Med, Yantai Key Lab Nanomed & Adv Preparat, Yantai 264000, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Qing,Chen, Lin-hai,Yang, Hui,et al. GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages[J]. ACTA PHARMACOLOGICA SINICA,2021:13.
APA	Zhang, Qing.,Chen, Lin-hai.,Yang, Hui.,Fang, You-chen.,Wang, Si-wei.,...&Xie, Xin.(2021).GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages.ACTA PHARMACOLOGICA SINICA,13.
MLA	Zhang, Qing,et al."GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages".ACTA PHARMACOLOGICA SINICA (2021):13.