GPR15 explained

G protein-coupled receptor 15 is a protein that in humans is encoded by the GPR15 gene.

GPR15 is a class A orphan G protein-coupled receptor (heterotrimeric guanine nucleotide-binding protein, GPCR). The GPR15 gene is localized at chromosome 3q11.2-q13.1.^{[1] [2]} It is found in epithelial cells,^[3] synovial macrophages,^[4] endothelial cells ^[5] and lymphocytes especially T cells. From the mRNA sequence a 40.8 kD molecular weight of GPR15 is proposed. In an epithelial tumour cell line (HT-29), however, a 36 kD band, composed of GPR15 and galactosyl ceramide, was detected. ^[3] Protein expression in lymphocytes is strongly associated with hypomethylation of its gene. ^[6]

Tissue distribution

High gene expression was described for colonic mucosa, small bowel mucosa, liver and spleen. Moderate gene expression was found in blood, lymph node, thymus, testis and prostate. ^{[3] [7]} In peripheral blood, GPR15 is mainly found on T cells, especially on CD4+ T helper cells, and less prominent on B cells. ^[8] By immunohistochemistry GPR15 is found specifically in glandular cells of the stomach, α-cells of islet of Langerhans in pancreas, surface epithelium of small intestine and colon, hepatocytes in liver, tubular epithelium of the kidney and in diverse tumour tissues such as glioblastoma, melanoma, small cell lung carcinoma or colon carcinoma.

Function

The overall physiological role remains elusive. It seems to play a role in homing of single T cell types to the colon. In human, GPR15 controls together with α4β7-integrin the homing of effector T cells to the inflamed gut of ulcerative colitis. ^[9] With respect to the homing of GPR15-expressing immune cells to the colon there are divergent mechanisms between human and rodents like mouse. ^[10]

Ligands

There are at least two endogenous ligand found recently. One ligand encoded by the human gene GPR15LG was identified as a robust marker for psoriasis whose abundance decreased after therapeutic treatment with anti-interleukin-17 antibody. Transcripts of GPR15LG are abundant in cervix and colon. It is currently unknown whether GPR15LG causes disease symptoms or is the consequence of a disturbed epithelial barrier. It does not act as a chemotactic agent but rather decrease T cell migration suggesting a mechanism of heterologous receptor desensitization. ^[11] The second ligand is a fragment of thrombomodulin exerting anti-inflammatory function in mice. ^[5]

Clinical significance

Human GPR15 was originally cloned as a co-receptor for HIV or the simian immunodeficiency virus. ^[7] HIV-induced activation of GPR15 in enterocytes seems to cause HIV enteropathy accompanied with diarrhea and lipid malabsorption. ^[3] In inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis the proportion of GPR15-expressing cells among regulatory T cells is slightly increased in peripheral blood. ^[9] In mouse, GPR15-deficient mice were prone to develop severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient T regs. ^[12]

Lifestyle

Chronic tobacco smoking is a very strong inducer of GPR15-expressing T cells in peripheral blood. Although the proportion of GPR15-expressing cells among T-cells in peripheral blood is a high sensitive and specific biomarker for chronic tobacco smoking ^[8] it does not indicate a disturbed homeostasis in the lung. ^[13]

Further reading

• Cunningham AL, Li S, Juarez J, Lynch G, Alali M, Naif H . The level of HIV infection of macrophages is determined by interaction of viral and host cell genotypes . Journal of Leukocyte Biology . 68 . 3 . 311–317 . September 2000 . 10.1189/jlb.68.3.311 . 10985245 . 38354228 . vanc .
• Deng HK, Unutmaz D, KewalRamani VN, Littman DR . Expression cloning of new receptors used by simian and human immunodeficiency viruses . Nature . 388 . 6639 . 296–300 . July 1997 . 9230441 . 10.1038/40894 . 4369660 . free . 1997Natur.388..296D .
• Farzan M, Choe H, Martin K, Marcon L, Hofmann W, Karlsson G, Sun Y, Barrett P, Marchand N, Sullivan N, Gerard N, Gerard C, Sodroski J . 6 . Two orphan seven-transmembrane segment receptors which are expressed in CD4-positive cells support simian immunodeficiency virus infection . The Journal of Experimental Medicine . 186 . 3 . 405–411 . August 1997 . 9236192 . 2198994 . 10.1084/jem.186.3.405 . vanc .
• Clayton F, Kotler DP, Kuwada SK, Morgan T, Stepan C, Kuang J, Le J, Fantini J . 6 . Gp120-induced Bob/GPR15 activation: a possible cause of human immunodeficiency virus enteropathy . The American Journal of Pathology . 159 . 5 . 1933–1939 . November 2001 . 11696454 . 1867054 . 10.1016/S0002-9440(10)63040-4 . vanc .
• Croitoru-Lamoury J, Guillemin GJ, Boussin FD, Mognetti B, Gigout LI, Chéret A, Vaslin B, Le Grand R, Brew BJ, Dormont D . 6 . Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation . Glia . 41 . 4 . 354–370 . March 2003 . 12555203 . 10.1002/glia.10181 . vanc . 85650574 .
• Maresca M, Mahfoud R, Garmy N, Kotler DP, Fantini J, Clayton F . The virotoxin model of HIV-1 enteropathy: involvement of GPR15/Bob and galactosylceramide in the cytopathic effects induced by HIV-1 gp120 in the HT-29-D4 intestinal cell line . Journal of Biomedical Science . 10 . 1 . 156–166 . 2003 . 12566994 . 10.1159/000068089 . vanc . 202645463 .
• Blaak H, Boers PH, Gruters RA, Schuitemaker H, van der Ende ME, Osterhaus AD . CCR5, GPR15, and CXCR6 are major coreceptors of human immunodeficiency virus type 2 variants isolated from individuals with and without plasma viremia . Journal of Virology . 79 . 3 . 1686–1700 . February 2005 . 15650194 . 544080 . 10.1128/JVI.79.3.1686-1700.2005 . vanc .
• Cilliers T, Willey S, Sullivan WM, Patience T, Pugach P, Coetzer M, Papathanasopoulos M, Moore JP, Trkola A, Clapham P, Morris L . 6 . Use of alternate coreceptors on primary cells by two HIV-1 isolates . Virology . 339 . 1 . 136–144 . August 2005 . 15992849 . 10.1016/j.virol.2005.05.027 . free . vanc . 25340368 . 20.500.11820/2faffa0f-11f3-4007-91d9-256e7c7f6051 .

Notes and References

1. Heiber M, Marchese A, Nguyen T, Heng HH, George SR, O'Dowd BF . A novel human gene encoding a G-protein-coupled receptor (GPR15) is located on chromosome 3 . Genomics . 32 . 3 . 462–465 . March 1996 . 8838812 . 10.1006/geno.1996.0143 .
2. Web site: Entrez Gene: GPR15 G protein-coupled receptor 15.
3. Clayton F, Kotler DP, Kuwada SK, Morgan T, Stepan C, Kuang J, Le J, Fantini J . 6 . Gp120-induced Bob/GPR15 activation: a possible cause of human immunodeficiency virus enteropathy . The American Journal of Pathology . 159 . 5 . 1933–1939 . November 2001 . 11696454 . 1867054 . 10.1016/S0002-9440(10)63040-4 .
4. Cartwright A, Schmutz C, Askari A, Kuiper JH, Middleton J . Orphan receptor GPR15/BOB is up-regulated in rheumatoid arthritis . Cytokine . 67 . 2 . 53–59 . June 2014 . 24725539 . 3996549 . 10.1016/j.cyto.2014.02.015 .
5. Pan B, Wang X, Nishioka C, Honda G, Yokoyama A, Zeng L, Xu K, Ikezoe T . 6 . G-protein coupled receptor 15 mediates angiogenesis and cytoprotective function of thrombomodulin . Scientific Reports . 7 . 1 . 692 . April 2017 . 28386128 . 5429650 . 10.1038/s41598-017-00781-w . 2017NatSR...7..692P .
6. Bauer M, Linsel G, Fink B, Offenberg K, Hahn AM, Sack U, Knaack H, Eszlinger M, Herberth G . 6 . A varying T cell subtype explains apparent tobacco smoking induced single CpG hypomethylation in whole blood . Clinical Epigenetics . 7 . 1 . 81 . 2015 . 26246861 . 4526203 . 10.1186/s13148-015-0113-1 . free .
7. Deng HK, Unutmaz D, KewalRamani VN, Littman DR . Expression cloning of new receptors used by simian and human immunodeficiency viruses . Nature . 388 . 6639 . 296–300 . July 1997 . 9230441 . 10.1038/40894 . 4369660 . free .
8. Bauer M, Hackermüller J, Schor J, Schreiber S, Fink B, Pierzchalski A, Herberth G . Specific induction of the unique GPR15 expression in heterogeneous blood lymphocytes by tobacco smoking . Biomarkers . 24 . 3 . 217–224 . May 2019 . 30387691 . 10.1080/1354750X.2018.1539769 . 53289288 .
9. Fischer A, Zundler S, Atreya R, Rath T, Voskens C, Hirschmann S, López-Posadas R, Watson A, Becker C, Schuler G, Neufert C, Atreya I, Neurath MF . 6 . Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo . Gut . 65 . 10 . 1642–1664 . October 2016 . 26209553 . 5036234 . 10.1136/gutjnl-2015-310022 .
10. Bilsborough J, Viney JL . GPR15: a tale of two species . Nature Immunology . 16 . 2 . 137–139 . February 2015 . 25594457 . 10.1038/ni.3084 . 28704425 .
11. Suply T, Hannedouche S, Carte N, Li J, Grosshans B, Schaefer M, Raad L, Beck V, Vidal S, Hiou-Feige A, Beluch N, Barbieri S, Wirsching J, Lageyre N, Hillger F, Debon C, Dawson J, Smith P, Lannoy V, Detheux M, Bitsch F, Falchetto R, Bouwmeester T, Porter J, Baumgarten B, Mansfield K, Carballido JM, Seuwen K, Bassilana F . 6 . A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia . Science Signaling . 10 . 496 . September 2017 . 28900043 . 10.1126/scisignal.aal0180 . 34911696 .
12. Kim SV, Xiang WV, Kwak C, Yang Y, Lin XW, Ota M, Sarpel U, Rifkin DB, Xu R, Littman DR . 6 . GPR15-mediated homing controls immune homeostasis in the large intestine mucosa . Science . 340 . 6139 . 1456–1459 . June 2013 . 23661644 . 3762262 . 10.1126/science.1237013 . 2013Sci...340.1456K .
13. Bauer M, Fink B, Seyfarth HJ, Wirtz H, Frille A . Tobacco-smoking induced GPR15-expressing T cells in blood do not indicate pulmonary damage . BMC Pulmonary Medicine . 17 . 1 . 159 . November 2017 . 29183299 . 5706341 . 10.1186/s12890-017-0509-0 . free .