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

文献类型：期刊论文

作者Zhang, Qing1,2; Chen, Lin-hai1; Yang, Hui1; Fang, You-chen1; Wang, Si-wei1,3; Wang, Min1; Yuan, Qian-ting1; Wu, Wei4; Zhang, Yang-ming5; Liu, Zhan-ju4
刊名ACTA PHARMACOLOGICA SINICA
出版日期2021-12-15
页码13
ISSN号1671-4083
关键词GPR84 medium chain fatty acid receptor GPCR inflammatory bowel diseases ulcerative colitis NLRP3 inflammasome macrophages
DOI10.1038/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
WOS关键词CHAIN FATTY-ACIDS ; PROTEIN-COUPLED RECEPTORS ; EXPERIMENTAL COLITIS ; MASTER REGULATORS ; SENSING RECEPTOR ; CROHNS-DISEASE ; BOWEL-DISEASE ; IMMUNE CELLS ; GUT ; PATHOGENESIS
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研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBL GROUP
WOS记录号WOS:000730502300002
源URL[http://119.78.100.183/handle/2S10ELR8/299169]  
专题新药研究国家重点实验室
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.

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来源：上海药物研究所

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