GPR183

EBI2 helps B cell homing to the outer follicular region within a lymph node. Approximately three hours following B cell exposure to plasma-soluble antigen, EBI2 is upregulated via the transcription factor BRRF1. More surface receptors binding the oxysterol ligand results in cellular migration up the gradient, to the outer follicular region. The reason for this early migration is still unknown; however, because soluble antigen enters lymph nodes via afferent lymphatic vasculature, near the outer region of the follicle, it is hypothesized that B cell movement is motivated by increased exposure to the antigen. Six hours after antigen exposure, EBI2 is downregulated to low levels, permitting the B cells to migrate to the border between the B cell and T cell zones of the lymph node. Here, B cells interact with T helper cells previously activated by antigen-presenting dendritic cells. Though CCR7 is the dominant receptor in this stage of B cell migration, EBI2 is still critical, the low expression of which contributes to organized interaction along the T zone border that maximizes interactions with T cells. Following B cell receptor and CD40 co-stimulation, EBI2 is again upregulated.{{cite journal | vauthors = Pereira JP, Kelly LM, Xu Y, Cyster JG | title = EBI2 mediates B cell segregation between the outer and centre follicle | journal = Nature | volume = 460 | issue = 7259 | pages = 1122–1126 | date = August 2009 | pmid = 19597478 | pmc = 2809436 | doi = 10.1038/nature08226 | bibcode = 2009Natur.460.1122P }} The B cells thus move back toward the outer follicular space, where they begin cell division. At this point, a B cell either downregulates EBI2 expression in order to enter a germinal center or maintains EBI2 expression and remains in outer follicular regions. In germinal centers (GC), B cells downregulate the receptor via the transcriptional repressor B-cell lymphoma-6 (BCL6) and, following somatic hypermutation, differentiate into long-lived antibody-secreting plasma cells or memory B cells. EBI2 must turn off to move B cells to the germinal center from the periphery, and must turn on for B cells to exit the germinal center and re-enter the periphery. Meanwhile, those remaining outside the follicle differentiate into plasmablasts, eventually becoming short-lived plasma cells. Thus, EBI2 expression modulates B cell differentiation by directing cells toward or away from germinal centers.

EBI2 also regulates intra-lymphatic T cell migration. Mature T helper cells upregulate EBI2 to follow the oxysterol gradient, migrating to the outer edges of the T cell zone to receive signals from antigen-presenting dendritic cells arriving from the tissues. This migration is critical as the resulting T cell-DC interaction induces T helper cell differentiation into T follicular helper cells.{{cite journal | vauthors = Willinger T | title = Oxysterols in intestinal immunity and inflammation | journal = Journal of Internal Medicine | volume = 285 | issue = 4 | pages = 367–380 | date = April 2019 | pmid = 30478861 | pmc = 7379495 | doi = 10.1111/joim.12855 }} In concert with upregulation of CXCR5, the downregulation of EBI2 helps T follicular helper cells move toward the follicle center to help B cells undergoing affinity maturation in germinal centers.

EBI2 expression on CD4+ dendritic cells is a key initiator of immune response. Antigen-activated dendritic cells are driven to lymph node bridging channels via the oxysterol-EBI2 pathway. In the spleen, bridging channels connect the marginal zone, where dendritic cells pick up plasma-soluble antigen, to the T cell zone, where they present antigen to T helper cells. This results in T cell proliferation and differentiation. Localization to bridging channels is also associated with dendritic cell reception of lymphotoxin beta signaling, which augments their blood pathogen uptake, resulting in an increase in T cell responses.

Oxysterols bind to and activate EBI2. The highest affinity oxysterol ligand is 7α,25-dihydroxycholesterol (7α,25-OHC), formed by enzymatic oxidation of cholesterol by the hydroxylases CH25H and CYP7B1. 7α,25-OHC is concentrated in bridging channels and the outer perimeter of B cell follicles. Conversely it is not present in follicle centers, germ centers, nor in the T zone. The enzymes responsible for ligand biosynthesis, CH25H and CYP7B1, are unsurprisingly abundant in lymphoid stromal cells. On the other hand, the enzyme that deactivates the ligand, HSD3B7, is highly concentrated in areas where the ligand concentration should be lowest—the T zone. Though it is not a cytokine, the EBI2 ligand acts much like a chemokine in that its gradient drives cellular migration.

GPR183 plays a crucial role in driving inflammation in the lungs during severe viral respiratory infections such as influenza A virus (IAV) and SARS-CoV-2. Studies using preclinical murine models of infection revealed that the activation of GPR183 by oxidized cholesterols leads to the recruitment of monocytes/macrophages and the production of inflammatory cytokines in the lungs.{{cite journal | vauthors = Foo CX, Bartlett S, Chew KY, Ngo MD, Bielefeldt-Ohmann H, Arachchige BJ, Matthews B, Reed S, Wang R, Smith C, Sweet MJ, Burr L, Bisht K, Shatunova S, Sinclair JE, Parry R, Yang Y, Lévesque JP, Khromykh A, Rosenkilde MM, Short KR, Ronacher K | display-authors = 6 | title = GPR183 antagonism reduces macrophage infiltration in influenza and SARS-CoV-2 infection | journal = The European Respiratory Journal | volume = 61 | issue = 3 | date = March 2023 | pmid = 36396144 | pmc = 9686317 | doi = 10.1183/13993003.01306-2022 }}

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• {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–174 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
• {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–156 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
• {{cite journal | vauthors = Rosenkilde MM, Benned-Jensen T, Andersen H, Holst PJ, Kledal TN, Lüttichau HR, Larsen JK, Christensen JP, Schwartz TW | display-authors = 6 | title = Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity | journal = The Journal of Biological Chemistry | volume = 281 | issue = 19 | pages = 13199–13208 | date = May 2006 | pmid = 16540462 | doi = 10.1074/jbc.M602245200 | doi-access = free }}

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{{G protein-coupled receptors}}

Category:G protein-coupled receptors

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