Gpr84-KO Mouse

Gpr84, a G protein-coupled receptor, is a medium-chain fatty acid receptor. It is involved in multiple physiological and pathological processes. Gpr84 signaling is related to inflammatory pathways and nutrient-sensing in metabolism, potentially modulating food intake [6].

In loss-of-function studies, Gpr84-KO mice showed increased lipid accumulation and reduced activity in brown adipose tissue (BAT), making them more vulnerable to cold. The in vitro experiments with primary brown adipocytes from Gpr84-KO mice indicated diminished thermogenic gene expression and reduced O₂ consumption. These findings suggest mitochondrial dysfunction as the cause of BAT anomalies in Gpr84-KO mice, highlighting Gpr84 as a potential target for metabolic disorder treatment [1].

In acute lung injury (ALI), Gpr84 deficiency or blockage significantly ameliorated lung inflammation in mice by reducing neutrophil infiltration and oxidative stress. Gpr84 -/- mice were also resistant to dextran sulfate sodium-induced colitis, with Gpr84 activation promoting pro-inflammatory properties in colonic macrophages [2,3].

In cancer, Gpr84 is overexpressed on myeloid-derived suppressor cells (MDSCs), and Gpr84 antagonism combined with an anti-PD-1 antibody enhanced antitumor responses. Additionally, Gpr84 transferred from MDSCs to CD8⁺ T cells via exosomes induced T-cell senescence through the p53 signaling pathway, suppressing the antitumor response [4,5].

In summary, Gpr84 plays crucial roles in metabolism, inflammation, and cancer-related immune responses. Gene knockout mouse models have revealed its significance in these biological processes and disease conditions, suggesting Gpr84 as a potential therapeutic target for metabolic disorders, ALI, ulcerative colitis, and enhancing anti-PD-1 immunotherapy efficacy in cancer [1-5].

References:

1. Sun, Xue-Nan, An, Yu A, Paschoal, Vivian A, Gupta, Rana K, Oh, Da Young. 2023. GPR84-mediated signal transduction affects metabolic function by promoting brown adipocyte activity. In The Journal of clinical investigation, 133, . doi:10.1172/JCI168992. https://pubmed.ncbi.nlm.nih.gov/37856216/

2. Wang, Si-Wei, Zhang, Qing, Lu, Dan, Nan, Fa-Jun, Xie, Xin. 2023. GPR84 regulates pulmonary inflammation by modulating neutrophil functions. In Acta pharmacologica Sinica, 44, 1665-1675. doi:10.1038/s41401-023-01080-z. https://pubmed.ncbi.nlm.nih.gov/37016043/

3. Zhang, Qing, Chen, Lin-Hai, Yang, Hui, Nan, Fa-Jun, Xie, Xin. 2021. GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages. In Acta pharmacologica Sinica, 43, 2042-2054. doi:10.1038/s41401-021-00825-y. https://pubmed.ncbi.nlm.nih.gov/34912006/

4. Qin, Guohui, Liu, Shasha, Liu, Jinyan, Zhang, Bin, Zhang, Yi. 2023. Overcoming resistance to immunotherapy by targeting GPR84 in myeloid-derived suppressor cells. In Signal transduction and targeted therapy, 8, 164. doi:10.1038/s41392-023-01388-6. https://pubmed.ncbi.nlm.nih.gov/37105980/

5. Liu, Jinyan, Liu, Jiayin, Qin, Guohui, Wang, Liping, Zhang, Yi. 2023. MDSCs-derived GPR84 induces CD8+ T-cell senescence via p53 activation to suppress the antitumor response. In Journal for immunotherapy of cancer, 11, . doi:10.1136/jitc-2023-007802. https://pubmed.ncbi.nlm.nih.gov/38016719/

6. Aktar, Rubina, Rondinelli, Silvia, Peiris, Madusha. 2023. GPR84 in physiology-Many functions in many tissues. In British journal of pharmacology, 181, 1524-1535. doi:10.1111/bph.16206. https://pubmed.ncbi.nlm.nih.gov/37533166/