Gpr183, also known as Epstein-Barr virus-induced gene 2, is a G-protein-coupled receptor for oxysterols and hydroxylated metabolites of cholesterol. It plays pleiotropic roles in lipid metabolism, immune responses, and is involved in various biological processes like immune cell positioning [3]. Oxysterols, such as 7α,25-dihydroxycholesterol (7α,25-OHC), act as its ligands, and the Gpr183-oxysterol axis is part of key signaling pathways [2,4,5,6,7,8,9].

Loss-of-function studies, including Gpr183 knockout mouse models, have revealed its significance in multiple disease conditions. In influenza A virus and SARS-CoV-2 infections, Gpr183 deficiency or treatment with its antagonist reduced macrophage infiltration and inflammatory cytokine production, attenuating disease severity [1]. In colitis models, Gpr183 inactivation lessened the severity in certain models and strongly reduced intestinal lymphoid tissue accumulation [5]. In hypertension, endothelial-specific Gpr183 knockout alleviated cardiovascular and renal injuries by reducing endothelial senescence [3].

In conclusion, Gpr183 is crucial in regulating immune responses, lymphoid tissue development, endothelial function, and pain perception. Gene knockout mouse models have been instrumental in highlighting its role in diseases such as severe viral respiratory infections, colitis, hypertension, and neuropathic pain, suggesting Gpr183 as a potential therapeutic target for these conditions [1,3,5,9].

References:

1. Foo, Cheng Xiang, Bartlett, Stacey, Chew, Keng Yih, Short, Kirsty R, Ronacher, Katharina. 2023. GPR183 antagonism reduces macrophage infiltration in influenza and SARS-CoV-2 infection. In The European respiratory journal, 61, . doi:10.1183/13993003.01306-2022. https://pubmed.ncbi.nlm.nih.gov/36396144/

2. Emgård, Johanna, Kammoun, Hana, García-Cassani, Bethania, Flavell, Richard A, Willinger, Tim. . Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation. In Immunity, 48, 120-132.e8. doi:10.1016/j.immuni.2017.11.020. https://pubmed.ncbi.nlm.nih.gov/29343433/

3. Chu, Qingqing, Li, Yujia, Wu, Jichao, Wang, Xiaojie, Yi, Fan. 2024. Oxysterol Sensing Through GPR183 Triggers Endothelial Senescence in Hypertension. In Circulation research, 135, 708-721. doi:10.1161/CIRCRESAHA.124.324722. https://pubmed.ncbi.nlm.nih.gov/39176657/

4. Frascoli, Michela, Ferraj, Enxhi, Miu, Bing, Kang, Joonsoo, Reboldi, Andrea. 2023. Skin γδ T cell inflammatory responses are hardwired in the thymus by oxysterol sensing via GPR183 and calibrated by dietary cholesterol. In Immunity, 56, 562-575.e6. doi:10.1016/j.immuni.2023.01.025. https://pubmed.ncbi.nlm.nih.gov/36842431/

5. Misselwitz, Benjamin, Wyss, Annika, Raselli, Tina, Pot, Caroline, Pabst, Oliver. 2021. The oxysterol receptor GPR183 in inflammatory bowel diseases. In British journal of pharmacology, 178, 3140-3156. doi:10.1111/bph.15311. https://pubmed.ncbi.nlm.nih.gov/33145756/

6. Bartlett, Stacey, Gemiarto, Adrian Tandhyka, Ngo, Minh Dao, Mandrup-Poulsen, Thomas, Ronacher, Katharina. 2020. GPR183 Regulates Interferons, Autophagy, and Bacterial Growth During Mycobacterium tuberculosis Infection and Is Associated With TB Disease Severity. In Frontiers in immunology, 11, 601534. doi:10.3389/fimmu.2020.601534. https://pubmed.ncbi.nlm.nih.gov/33240287/

7. Bohrer, Andrea C, Castro, Ehydel, Tocheny, Claire E, Klion, Amy D, Mayer-Barber, Katrin D. . Rapid GPR183-mediated recruitment of eosinophils to the lung after Mycobacterium tuberculosis infection. In Cell reports, 40, 111144. doi:10.1016/j.celrep.2022.111144. https://pubmed.ncbi.nlm.nih.gov/35905725/

8. Kjær, Viktoria M S, Daugvilaite, Viktorija, Stepniewski, Tomasz M, Selent, Jana, Rosenkilde, Mette M. 2023. Migration mediated by the oxysterol receptor GPR183 depends on arrestin coupling but not receptor internalization. In Science signaling, 16, eabl4283. doi:10.1126/scisignal.abl4283. https://pubmed.ncbi.nlm.nih.gov/37014928/

9. Braden, Kathryn, Giancotti, Luigino Antonio, Chen, Zhoumou, Arnatt, Christopher Kent, Salvemini, Daniela. 2020. GPR183-Oxysterol Axis in Spinal Cord Contributes to Neuropathic Pain. In The Journal of pharmacology and experimental therapeutics, 375, 367-375. doi:10.1124/jpet.120.000105. https://pubmed.ncbi.nlm.nih.gov/32913007/