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GPR84 regulates pulmonary inflammation by modulating neutrophil functions

Si-wei Wang1,2, Qing Zhang1,3,4, Dan Lu5, You-chen Fang1, Xiao-ci Yan1,2,3, Jing Chen1,2, Zhi-kan Xia1,2, Qian-ting Yuan1, Lin-hai Chen1, Yang-ming Zhang6, Fa-jun Nan1,3,4, Xin Xie1,2,3,4,5
1 State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
4 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China
5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
6 Burgeon Therapeutics Co., Ltd., Shanghai 201203, China
Correspondence to: Xin Xie: xxie@simm.ac.cn,
DOI: 10.1038/s41401-023-01080-z
Received: 25 January 2023
Accepted: 14 March 2023
Advance online: 4 April 2023

Abstract

Acute lung injury (ALI) is an acute, progressive hypoxic respiratory failure that could develop into acute respiratory distress syndrome (ARDS) with very high mortality rate. ALI is believed to be caused by uncontrolled inflammation, and multiple types of immune cells, especially neutrophils, are critically involved in the development of ALI. The treatment for ALI/ARDS is very limited, a better understanding of the pathogenesis and new therapies are urgently needed. Here we discover that GPR84, a medium chain fatty acid receptor, plays critical roles in ALI development by regulating neutrophil functions. GPR84 is highly upregulated in the cells isolated from the bronchoalveolar lavage fluid of LPS-induced ALI mice. GPR84 deficiency or blockage significantly ameliorated ALI mice lung inflammation by reducing neutrophils infiltration and oxidative stress. Further studies reveal that activation of GPR84 strongly induced reactive oxygen species production from neutrophils by stimulating Lyn, AKT and ERK1/2 activation and the assembly of the NADPH oxidase. These results reveal an important role of GPR84 in neutrophil functions and lung inflammation and strongly suggest that GPR84 is a potential drug target for ALI.
Keywords: GPR84; acute lung injury; inflammation; neutrophil; ROS; antagonist

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