|G protein-coupled receptor 84|
|Symbols||; EX33; GPCR4|
|External IDs||IUPHAR: GeneCards:|
GPR84 (EX33) was described practically in the same time by two groups. One was the group of Timo Wittenberger in the Zentrum fur Molekulare Neurobiologie, Hamburg, Germany (Wittenberg T. et al.) and the other was the group of Gabor Jarai in Novartis Horsham Research Centre, Horsham, United Kingdom. In their papers they described the sequence and expression profile of five new members of GPC receptor family. One among them was GPR84 which represents a unique GPCR sub-family so far.
Hgpr84 locates to chromosome 12q13.13, and its coding sequence is not interrupted by introns.
The human and the murine GPR84 ORFs both encode proteins of 396 amino acid residues length with 85% identity and are therefore considered as orthologs. The hgpr84 was found by Northern blot analysis as a transcript of about 1.5 kb in brain, heart, muscle, colon, thymus, spleen, kidney, liver, intestine, placenta, lung, and leukocytes. In addition, a 1.2 kb transcript in heart and a strong band at 1.3 kb in muscle were detected. A Northern blot from different brain regions revealed strongest expression of the 1.5 kb transcript in the medulla and the spinal cord. Somewhat less transcript was found in the substantia nigra, thalamus, and the corpus callosum. The 1.5 kb band was also visible in other brain regions, but at very low levels. EST clones corresponding to hgpr84 were from B cells (leukemia), neuroendocrine lung as well as in microglial cells and adipocytes. A more detailed description of expression profile can be found in www.genecards.org. The resting expression of GPR84 is usually low but it is highly inducible in inflammation. Its expression on neutrophils can be increased with LPS stimulation and reduced with GM-CSF stimulation. The LPS-induced upregulation of GPR84 was not sensitive to dexamathasone pretreatment. There was also a GPR84 downregulation in dentritic cell derived from FcRgamma chain KO mice. In microglial cells, the GPR84 induction with interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) was also demonstrated. 24 h treatment with IL-1β also induced 5.8 times increase in GPR84 expression on PBMC from healthy individuals. . Transcriptional dynamics of human umbilical cord blood T helper cells cultured in absence and presence of cytokines promoting Th1 or Th2 differentiation was studies. It turned out that GPR84 belongs to the Th1 specific subset genes. While another publication suggests that GPR84 is rather a CCL1 related Th2 type gene.
GPR84 was also upregulated on both macrophages and neutrophyl granulocytes after LPS stimulation. Not only LPS challenge but Staphylococcus enterotoxin B was sufficient to cause a 50 times increase in GPR84 expression on isolated human leukocytes stimulated with compared to the expression of naive leukocytes. A viral infection following Japanese encephalitis virus infection also increased GPR84 expression by 2-4.5% in the mice brain.
Ablating lysosomal acid lipase (Lal-/-) in mice led to aberrant expansion of myeloid-derived suppressive cells (MDSCs) (>40% in the blood, and >70% in the bone marrow) that arise from dysregulated production of myeloid progenitor cells in the bone marrow. Ly6G + MDSCs in Lal-/- mice show strong immunosuppression on T cells, which contributes to impaired T cell proliferation and function in vivo. GPR84 was 9.1 fold upregulated in the MDSCs of Lal-/- mice. GPR84 is normally expressed at low levels in myeloid cells and can be induced in vitro by stimulating macrophage or microglial cells with LPS, TNFα, or PMA. Elevated expression of GPR84 was also observed during the demyelination phase of the reversible Cuprizone-Induced Demyelinating Disease mouse model. Finally, it has also shown that GPR84 expression is increased in both the normal appearing white matter and plaque in brains from human Multiple Sclerosis patients. Expression of GPR84 increases in mouse whole brain samples from experimental autoimmune encephalomyelitis before the onset of clinical disease. In cultured microglia in response to simulated blast overpressure the expression of GPR84 was increased 2.9 fold. In ageing TgSwe mice were subjected to traumatic brain injury GPR84 was upregulated by 6.3 fold. GPR84 expression was increased by 49.9 times in M1 type macrophages isolated from aortic atherosclerotic lesions of LDLR-/- mice were fed a western diet. GPR84 is important in regulating the expression of cytokines: CD4+ T cells from GPR84-/- mice show increase IL-4 secretion in the presence of anti-CD3 and anti-CD28 antibodies; GPR84 potentiates LPS-induced IL12p40 secretion in RAW264.7 cells. Recent work by Nagasaki et al. explored 3T3-L1 adipocytes cocultured with RAW264.7 cells to examine this potential interaction. RAW264.7 coculture increases GPR84 expression in 3T3-L1 adipocytes, and incubation with capric acid can inhibit TNFα-induced adiponectin release. Adiponectin regulates many metabolic processes associated with glucose and fatty acids, including insulin sensitivity and lipid breakdown. Furthermore, a high-fat diet can increase GPR84 expression. The authors suggest that GPR84 may explain the relationship between diabetes and obesity. As adipocytes release fatty acids in the presence of macrophages, the loop of increased GPR84 expression and its stimulation prevent the release of regulating hormones. The work on GPR84 is still very early and needs to be expanded in the context of pathophysiology and immune regulation. Some people presume the role of GPR84 in food intake too. GPR84 is expressed in the gastric corpus mucosa and this receptor can be an important luminal sensors of food intake and are most likely expressed on entero-endocrine cells, where it stimulates the release of peptide hormones including incretins glucagon-like peptide (GLP) 1 and 2.
The ligands for GPR84 suggest also a relationship between inflammation and fatty acid sensing or regulation. Medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent described endogeneous agonists of GPR84. Not activated by short-chain and long-chain saturated and unsaturated FFAs induced in onocytes/macrophages by LPS. In addition, the activation of GPR84 in monocytes/macrophages amplifies LPS stimulated IL-12 p40 production in a concentration dependent manner. IL-12 plays an important role in promoting cell mediated immunity to eradicate pathogens by inducing and maintaining T helper 1 responses and inhibiting T helper 2 responses. Medium chain FFAs inhibited forskolin-induced cAMP production and stimulated [35S]GTPgammaS binding in a GPR84-dependent manner. The EC50 values for medium-chain FFAs capric acid, undecanoic acid, and lauric acid at GPR84 (4, 8, and 9 mM, respectively, in the cAMP assay). These results suggest that GPR84 activation by medium-chain FFAs is coupled to a pertussis toxin-sensitive Gi/o pathway. Besides medium-chain FFAs diindolylmethane was also described as GPR84 agonist. However, the target selectivity of this molecule is also questionable because diindolylmethane is an aryl hydrocarbon receptor modulator, too. Interestingly, the patent literature mentions that besides medium chain FFAs other substances as 2,5-Dihydroxy-3-undecyl(1,4)benzoquinon, Icosa-5,8,11,14-tetraynoic acid and 5S,6R-Dihydroxy-icosa-7,9,11,14-tetraenoic acid (5S,6RdiHETE) are also ligands of GPR84. These two latest molecules say against the statement that long chain FFAs are not ligands of GPR84. Based on these results it is probable that besides medium chain FFAs some long chain FFAs can also be endogeneous ligands of GPR84. Further work is needed to confirm this hypothesis.
Drugs under investigation
The molecule GLPG1205 is currently (2015) under investigation by the Belgian firm Gálapagos. Its clinical effect against inflammatory disorders like inflammatory bowel disease is being investigated in a Phase 2 Proof-of-Concept study in ulcerative colitis patients. According to the company, the results of this study will be available in 2016.
- Wittenberger T, Schaller HC, Hellebrand S (Mar 2001). "An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors". J Mol Biol 307 (3): 799–813. doi:10.1006/jmbi.2001.4520. PMID 11273702.
- "Entrez Gene: GPR84 G protein-coupled receptor 84".
- Bouchard C, Pagé J, Bédard A, Tremblay P, Vallières L (June 2007). "G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditions". Glia 55 (8): 790–800. doi:10.1002/glia.20506. PMID 17390309.
- Nagasaki H, Kondo T, Fuchigami M, Hashimoto H, Sugimura Y, Ozaki N, Arima H, Ota A, Oiso Y, Hamada Y (February 2012). "Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFα enhances GPR84 expression in adipocytes". FEBS Lett. 586 (4): 368–72. doi:10.1016/j.febslet.2012.01.001. PMID 22245676.
- van Montfoort N, ‘t Hoen PAC, Camps M, Melief CJM, Ossendorp F, Verbeek JS. "FcgR Ligation on Dendritic Cells induces Broad Immune Response Gene Signature Tightly Regulated by FcgRIIb" (PDF).
- Aijö T, Edelman SM, Lönnberg T, Larjo A, Kallionpää H, Tuomela S, Engström E, Lahesmaa R, Lähdesmäki H (2012). "An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiation". BMC Genomics 13: 572. doi:10.1186/1471-2164-13-572. PMC 3526425. PMID 23110343.
- Smeets RL, Fleuren WW, He X, Vink PM, Wijnands F, Gorecka M, Klop H, Bauerschmidt S, Garritsen A, Koenen HJ, Joosten I, Boots AM, Alkema W (2012). "Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling". BMC Immunol. 13: 12. doi:10.1186/1471-2172-13-12. PMC 3355027. PMID 22413885.
- Lattin JE, Schroder K, Su AI, Walker JR, Zhang J, Wiltshire T, Saijo K, Glass CK, Hume DA, Kellie S, Sweet MJ (2008). "Expression analysis of G Protein-Coupled Receptors in mouse macrophages". Immunome Res 4: 5. doi:10.1186/1745-7580-4-5. PMC 2394514. PMID 18442421.
- Sethu P, Moldawer LL, Mindrinos MN, Scumpia PO, Tannahill CL, Wilhelmy J, Efron PA, Brownstein BH, Tompkins RG, Toner M (August 2006). "Microfluidic isolation of leukocytes from whole blood for phenotype and gene expression analysis". Anal. Chem. 78 (15): 5453–61. doi:10.1021/ac060140c. PMID 16878882.
- Gupta N, Rao PV (2011). "Transcriptomic profile of host response in Japanese encephalitis virus infection". Virol. J. 8: 92. doi:10.1186/1743-422X-8-92. PMC 3058095. PMID 21371334.
- Gray JC, Potthoff B, Beckmann H, Kayser F, Escobar S, Mozaffarian A, Arnett HA, Kirchner J, Wang S. "GPR84, a receptor expressed on myeloid cells and a potential target for treatment of Multiple Sclerosis". Program#/Poster#: 824.26/D5.
- Kane MJ, Angoa-Pérez M, Francescutti DM, Sykes CE, Briggs DI, Leung LY, VandeVord PJ, Kuhn DM (July 2012). "Altered gene expression in cultured microglia in response to simulated blast overpressure: possible role of pulse duration". Neurosci. Lett. 522 (1): 47–51. doi:10.1016/j.neulet.2012.06.012. PMID 22698585.
- Israelsson C, Bengtsson H, Lobell A, Nilsson LN, Kylberg A, Isaksson M, Wootz H, Lannfelt L, Kullander K, Hillered L, Ebendal T (March 2010). "Appearance of Cxcl10-expressing cell clusters is common for traumatic brain injury and neurodegenerative disorders". Eur. J. Neurosci. 31 (5): 852–63. doi:10.1111/j.1460-9568.2010.07105.x. PMID 20374285.
- Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR, Elliott MR, Gruber F, Han J, Chen W, Kensler T, Ravichandran KS, Isakson BE, Wamhoff BR, Leitinger N (September 2010). "Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2". Circ. Res. 107 (6): 737–46. doi:10.1161/CIRCRESAHA.109.215715. PMC 2941538. PMID 20651288.
- Venkataraman C, Kuo F (November 2005). "The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking". Immunol. Lett. 101 (2): 144–53. doi:10.1016/j.imlet.2005.05.010. PMID 15993493.
- Wang J, Wu X, Simonavicius N, Tian H, Ling L (November 2006). "Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84". J. Biol. Chem. 281 (45): 34457–64. doi:10.1074/jbc.M608019200. PMID 16966319.
- Goebel M, Stengel A, Lambrecht NW, Sachs G (March 2011). "Selective gene expression by rat gastric corpus epithelium". Physiol. Genomics 43 (5): 237–54. doi:10.1152/physiolgenomics.00193.2010. PMC 3068518. PMID 21177383.
- Yin XF, Chen J, Mao W, Wang YH, Chen MH (2012). "A selective aryl hydrocarbon receptor modulator 3,3'-Diindolylmethane inhibits gastric cancer cell growth". J. Exp. Clin. Cancer Res. 31: 46. doi:10.1186/1756-9966-31-46. PMC 3403951. PMID 22592002.
- WO application 2007027661, Hakak Y, Unett DJ, Gatlin J, Liaw CW, "Human G protein-coupled receptor and modulators thereof for the treatment of atherosclerosis and atherosclerotic disease and for the treatment of conditions related to MCP-1 expression", published 2007-08-03, assigned to Arena Pharmaceuticals
- Yousefi S, Cooper PR, Potter SL, Mueck B, Jarai G (June 2001). "Cloning and expression analysis of a novel G-protein-coupled receptor selectively expressed on granulocytes". J. Leukoc. Biol. 69 (6): 1045–52. PMID 11404393.
- Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S (June 2002). "Identification of G protein-coupled receptor genes from the human genome sequence". FEBS Lett. 520 (1-3): 97–101. doi:10.1016/S0014-5793(02)02775-8. PMID 12044878.