Biology:GPR84

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Probable G-protein coupled receptor 84 is a protein that in humans is encoded by the GPR84 gene.[1][2]

Discovery

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.

Gene

Hgpr84 locates to chromosome 12q13.13, and its coding sequence is not interrupted by introns.[1]

Protein

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.[1] 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[3] and adipocytes.[4] 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.[5] In microglial cells, the GPR84 induction with interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) was also demonstrated.[3] 24 h treatment with IL-1β also induced 5.8 times increase in GPR84 expression on PBMC from healthy individuals.[citation needed] . 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.[6] While another publication suggests that GPR84 is rather a CCL1 related Th2 type gene.[7]

GPR84 was also upregulated on both macrophages and neutrophyl granulocytes after LPS stimulation.[8] 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.[9] A viral infection following Japanese encephalitis virus infection also increased GPR84 expression by 2-4.5% in the mice brain.[10]

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.[11] In cultured microglia in response to simulated blast overpressure the expression of GPR84 was increased 2.9 fold.[12] In ageing TgSwe mice were subjected to traumatic brain injury GPR84 was upregulated by 6.3 fold.[13] 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.[14] 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;[15] GPR84 potentiates LPS-induced IL12p40 secretion in RAW264.7 cells.[16] Recent work by Nagasaki et al. explored 3T3-L1 adipocytes cocultured with RAW264.7 cells to examine this potential interaction.[4] 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.[17]

Ligands

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[16] described endogeneous agonists of GPR84. Not activated by short-chain and long-chain saturated and unsaturated FFAs induced in monocytes/macrophages by LPS. In addition, the activation of GPR84 in monocytes/macrophages amplifies LPS stimulated IL-12 p40 production in a concentration dependent manner.[16] 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.[16] 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.[16] However, the target selectivity of this molecule is also questionable because diindolylmethane is an aryl hydrocarbon receptor modulator, too.[18] 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.[19] 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.

Classification of GPR84

Based on its binding and activation by medium-chain fatty acids, GPR84 has been recognized as a possible member of the free fatty acid receptor family.[20] However, GPR84 has not yet been given a FFAR designation possibly because capric acid, the most potent medium-chain fatty acid in activating GPR44, requires high concentrations (e.g., in the micromolar range) to do so. This consideration supports the need to search for other naturally-occurring agents that are more potent than caproic acid in activating this receptor.[21] In the meantime, GPR84 continues to be defined as an orphan receptor, i.e., a receptor who's naturally occurring activator(s) is unclear.[22]

Major mediator in pathologic fibrotic pathways

GPR84 has been proposed to be a major mediator in pathologic fibrotic pathways.[23]

Drugs under investigation

The molecule GLPG1205 was under investigation by the Belgian firm Galapagos NV. Its clinical effect against inflammatory disorders like inflammatory bowel disease was being investigated in 2015 in a Phase 2 Proof-of-Concept study in ulcerative colitis patients. The results published in January 2016 showed good pharmacokinetics, safety and tolerability. However, the target efficacy was not met. The development of GLPG1205 for ulcerative colitis was therefore stopped.[24]

The molecule PBI-4050 which inhibits GPR84 signaling is under investigation by the Canadian biotechnology firm Prometic. As of August 2018, it remains a promising drug targeting multiple type of fibrosis entering phase 3 clinical trials.[25]

References

  1. ↑ 1.0 1.1 1.2 "An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors". Journal of Molecular Biology 307 (3): 799–813. March 2001. doi:10.1006/jmbi.2001.4520. PMID 11273702. 
  2. ↑ "Entrez Gene: GPR84 G protein-coupled receptor 84". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=53831. 
  3. ↑ 3.0 3.1 "G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditions". Glia 55 (8): 790–800. June 2007. doi:10.1002/glia.20506. PMID 17390309. 
  4. ↑ 4.0 4.1 "Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFα enhances GPR84 expression in adipocytes". FEBS Letters 586 (4): 368–72. February 2012. doi:10.1016/j.febslet.2012.01.001. PMID 22245676. 
  5. ↑ van Montfoort N; ‘t Hoen PAC; Camps M; Melief CJM; Ossendorp F; Verbeek JS (25 November 2010). FcgR Ligation on Dendritic Cells induces Broad Immune Response Gene Signature Tightly Regulated by FcgRIIb (PDF) (Thesis). Leiden University.
  6. ↑ "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. October 2012. doi:10.1186/1471-2164-13-572. PMID 23110343. 
  7. ↑ "Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling". BMC Immunology 13: 12. March 2012. doi:10.1186/1471-2172-13-12. PMID 22413885. 
  8. ↑ "Expression analysis of G Protein-Coupled Receptors in mouse macrophages". Immunome Research 4: 5. April 2008. doi:10.1186/1745-7580-4-5. PMID 18442421. 
  9. ↑ "Microfluidic isolation of leukocytes from whole blood for phenotype and gene expression analysis". Analytical Chemistry 78 (15): 5453–61. August 2006. doi:10.1021/ac060140c. PMID 16878882. 
  10. ↑ "Transcriptomic profile of host response in Japanese encephalitis virus infection". Virology Journal 8: 92. March 2011. doi:10.1186/1743-422X-8-92. PMID 21371334. 
  11. ↑ "GPR84, a receptor expressed on myeloid cells and a potential target for treatment of Multiple Sclerosis". Program#/Poster#: 824.26/D5. 
  12. ↑ "Altered gene expression in cultured microglia in response to simulated blast overpressure: possible role of pulse duration". Neuroscience Letters 522 (1): 47–51. July 2012. doi:10.1016/j.neulet.2012.06.012. PMID 22698585. 
  13. ↑ "Appearance of Cxcl10-expressing cell clusters is common for traumatic brain injury and neurodegenerative disorders". The European Journal of Neuroscience 31 (5): 852–63. March 2010. doi:10.1111/j.1460-9568.2010.07105.x. PMID 20374285. 
  14. ↑ "Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2". Circulation Research 107 (6): 737–46. September 2010. doi:10.1161/CIRCRESAHA.109.215715. PMID 20651288. 
  15. ↑ "The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking". Immunology Letters 101 (2): 144–53. November 2005. doi:10.1016/j.imlet.2005.05.010. PMID 15993493. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 "Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84". The Journal of Biological Chemistry 281 (45): 34457–64. November 2006. doi:10.1074/jbc.M608019200. PMID 16966319. 
  17. ↑ "Selective gene expression by rat gastric corpus epithelium". Physiological Genomics 43 (5): 237–54. March 2011. doi:10.1152/physiolgenomics.00193.2010. PMID 21177383. 
  18. ↑ "A selective aryl hydrocarbon receptor modulator 3,3'-Diindolylmethane inhibits gastric cancer cell growth". Journal of Experimental & Clinical Cancer Research 31 (1): 46. May 2012. doi:10.1186/1756-9966-31-46. PMID 22592002. 
  19. ↑ 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", WO patent application 2007027661, published 2007-08-03, assigned to Arena Pharmaceuticals
  20. ↑ "Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors". Frontiers in Cellular Neuroscience 13: 162. 2019. doi:10.3389/fncel.2019.00162. PMID 31105530. 
  21. ↑ "20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?". DNA and Cell Biology 39 (11): 1926–1937. November 2020. doi:10.1089/dna.2020.5846. PMID 33001759. 
  22. ↑ "GPR84 in physiology-Many functions in many tissues". British Journal of Pharmacology. August 2023. doi:10.1111/bph.16206. PMID 37533166. 
  23. ↑ "A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84". The American Journal of Pathology 188 (5): 1132–1148. May 2018. doi:10.1016/j.ajpath.2018.01.009. PMID 29454750. 
  24. ↑ "Galapagos reports results with GLPG1205 in ulcerative colitis". Galapagos. 26 January 2016. http://www.glpg.com/docs/view/56a70f4ad23cf-en. 
  25. ↑ "A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84". The American Journal of Pathology 188 (5): 1132–1148. May 2018. doi:10.1016/j.ajpath.2018.01.009. PMID 29454750. 

Further reading



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