GPR84 - Protein

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. 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.