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Gas-Coupled Gpcrs GPR65 and GPR174. Downers for Immune Responses Remy Robert & Charles R Mackay

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Gas-Coupled Gpcrs GPR65 and GPR174. Downers for Immune Responses Remy Robert & Charles R Mackay Immunology & Cell Biology 2018; 96: 341–343 www.wileyonlinelibrary.com/journal/icb NEWS AND COMMENTARY Gas-coupled GPCRs GPR65 and GPR174. Downers for immune responses Remy Robert & Charles R Mackay Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia Immunology & Cell Biology 2018; 96: 341–343; doi: 10.1111/imcb.12027 There are about 1000 different GPCRs, emphasizing the importance of proton Gai ¼ Adenylate Cyclase inhibition many of them labeled GPR123 and so sensing for immune regulation. ¼ i forth, so perhaps, one wonders, why GPR174 on the other hand is a cAMP nhibition wastetimeontwoobscureones— receptor for a phosphatidylserine ¼ immune cell inciting ðthink GPR65 and GPR174? Well, these two metabolite, lysophosphatidylserine inflammatory chemokine receptors share a fascinating feature— (LysoPS). Not much is known about receptors, for exampleÞ: they are widely expressed by immune this metabolite and why its presence cells and appear to be important may be immuno-regulating. Wirasinha et al.4, in a paper recently regulators of immunity, i.e. anti- What connects GPR65 and published in Immunology & Cell inflammatory. Indeed, the brakes GPR174 is that they appear to be two Biology, found that GPR65 plays an applied to immune responses by these of the most widely expressed GPCRs important role in demyelinating two receptors put them up there with that signal through the G-protein, autoimmune disease. They used Treg cells, and metabolite-sensing Gas (see Figure 1). Signaling through the typical murine model of MS, 1 receptors such as GPR43, as Gas leads to cAMP production, experimental autoimmune encephalo- regulators of immunity. In support of which is (usually) anti-inflammatory. myelitis (with all its admitted this, genetic polymorphisms in GPR65 Few GPCRs expressed on immune limitations), and found that Gpr65- associate with many inflammatory cells signal through Gas—most like deficient mice developed exacerbated diseases, sometimes more so than the chemokine receptors signal disease. They used a green fluorescent the MHC (particularly inflammatory through Gai. protein reporter mouse (Gpr65gfp/gfp)to bowel diseases). Gas-mediated activation of show that GPR65 is likely expressed at GPR65 is a proton sensor, so it adenylate cyclase leads to very high levels by invariant natural senses pH, hence conditions such as accumulation of cAMP, particularly in killer T (iNKT) cells. They showed that acidosis or high acid exposure (for inflammatory immune cells like experimental autoimmune encephalo- instance in the gastrointestinal tract) neutrophils and eosinophils. cAMP myelitis severity in Gpr65-deficient control its activity, and signaling can do various things, one of which is mice was normalized in the contributes to gut and immune lead to phosphorylation of the absence of iNKT cells (using homeostasis. Mutation in another transcription factor CREB (cAMP CD1d-deficient mice), suggesting that proton-sensing Gpr65 family member, response element-binding protein), GPR65 signals in iNKT cells were Gpr132, leads to the development of a which controls many things, including particularly important for suppressing 2 3 lupus-like disease in mice further numerous inflammatory cytokines. A this autoimmune condition. These convenient way to remember this results in experimental autoimmune Correspondence important dichotomy in GPCR encephalomyelitis follow several other Charles R Mackay, Infection and Immunity signaling, and immune suppression studies that have shown that absence Program, and Department of Microbiology, versus incitement, is as follows: of GPR65 exacerbates inflammation, Biomedicine Discovery Institute, Monash a ¼ A s 5 University, Building75, Rm 372, Wellington G s denylate Cyclase timulation particularly in colitis models, which Rd, Clayton, VIC 3800 Australia. ¼ cAMP supply may relate to pH sensing in the lower E-mail: [email protected] ¼ immune cell suppression gastrointestinal tract. 341 Gas-coupled GPCRs GPR65 GPR174 R Robert & CR Mackay Gαs-coupled GPCRs GPR65, GPR174, A2aR (and others) Adenylate cyclase Control of gene transcripon -IL-2 - Inflammatory cytokines -Cell migraon P γ Gβ G PKA Gαs CREB X Increase in cAMP Transcripon factor phosphorylated CREB binding site in gene promoters Figure 1. Gas-coupled GPCRs and the basics of downstream events. Some of the main Gas-coupled GPCRs on immune cells are GPR65, GPR174 and A2aR. These selectively signal through Gas which activates adenylate cyclase and results in cAMP increase. cAMP via protein kinase A (PKA) leads to phosphorylation of CREB (cAMP response element-binding protein) a transcription factor that binds to DNA sequences in promoter or enhancer regions, thereby increasing or decreasing the transcription of downstream genes. Notably, immune genes affected by CREB include IL-2, and certain inflammatory cytokines. A fuzzy picture was emerging, at is suppressed. Indeed, LysoPS has inflammatory disease. It appears that this point, that maybe GPR65 was been known for some years to be GPR65 may be one of those pivotal the main Gas-coupled GPCR involved in inflammation resolution. molecules for immune responses expressed on immune cells, and LysoPS does various things in (think immune response gene), that this receptor alone was addition to its effects on T cells. It which determines the quality of an the immunosuppressive, cAMP enhances the clearance of apoptotic immune response and the balance supplying GPCR for immune cells. neutrophils from inflammatory sites- between anti-pathogen versus And that acidosis was a major all consistent with inflammation autoimmune responses. GPCRs are mechanism for suppression of suppression or resolution.8 good drug targets, but should one immune cell functions. However, in What lies ahead for GPR65 and agonize or antagonize GPR65? It a paper published in this issue of GPR174? Probing the associations of probably depends on the indication, Immunology & Cell Biology,6 Barnes the minor allele of Gpr65, (the IBD- and as Wirasinha et al. show, and Cyster report on the impressive associated missense variant GPR65 agonism may aid in immune-suppressive activity of rs3742704, which encodes an treatment of experimental auto- LysoPS and its receptor GPR174. isoleucine-to-leucine substitution at immune encephalomyelitis/MS. They used in vivo models of T-cell amino acid 231) which leads to less Agonism of GPR65 would proliferation, which were induced by signaling and cAMP production,5 presumably also be of benefit for sublethal irradiation, or depletion of with other inflammatory diseases is inflammatory bowel diseases.5 Tregs. When GPR174 was expressed an obvious next step. Does Design of small molecule agonists on T cells, T-cell proliferation was rs3742704 associate with other major for topical delivery to the GI tract constrained, whereas GPR174 human inflammatory diseases? Does may be a good strategy, and deletion resulted in much greater GPR65 play a role in anti-tumor polymorphisms in GPR65 (which T-cell proliferation. They next responses? Presumably something is limit Gas signaling) associate with showed that GPR174 couples with driving the maintenance of the both Crohn’s disease and ulcerative Gas to mediate suppression of T-cell minor allele in humans, because it is colitis. Agonist small molecule drugs proliferation. They showed that present at a reasonably high for GPR65 have been produced9 LysoPS and GPR174/Gas suppressed frequency across all ethnicities. Poor but are yet to advance to human IL-2 production by activated T cells, GPR65 signaling and less cAMP clinical trials (as far as we know). and limited upregulation of CD25 production, which associate with the For GPR174, knowledge on the and CD69. Interestingly, the IL-2 minor allele,5 may aid anti-tumor or biology of LysoPS is lacking, and promoter contains a CREB binding anti-pathogen immune responses. why this metabolite is a natural site,7 which presumably is the The flip-side is over-zealous suppressor of T-cell responses is mechanism whereby IL-2 production inflammatory responses, and unknown. 342 R Robert & CR Mackay Gas-coupled GPCRs GPR65 GPR174 Finally, we would like to make some REFERENCES 6. Barnes M, Cyster J. Lyso- speculative predictions. One is that phosphatidylserine suppression of T 1. Tan JK, McKenzie C, Marino E, immune modifying drugs will emerge cell activation via GPR174 requires et al. Metabolite-sensing G protein- a that target GPR65 or GPR174, and so G s proteins. Immunol Cell Biol coupled receptors—facilitators of 2018; 96: 439–445. modify immune responses for diet-related immune regulation. 7. Powell JD, Lerner CG, Ewoldt GR, inflammatory diseases, or cancer. Annu Rev Immunol 2017; 35: 371– et al. The -180 site of the IL-2 These receptors appear to be great 402. promoter is the target of CREB/ targets. Agonists would find use for 2. Le LQ, Kabarowski JH, Weng Z, et al. CREM binding in T cell anergy. J suppressing inflammatory diseases, Mice lacking the orphan G protein- Immunol 1999; 163: 6631–6639. whereas antagonists might be of use in coupled receptor G2A develop a late- 8. Frasch SC, Bratton DL. Emerging boosting immune responses, for onset autoimmune syndrome. roles for lysophosphatidylserine in Immunity 2001; 14:561–571. immuno-oncology. Another Gas- resolution of inflammation. Prog 3. Wen AY, Sakamoto KM, Miller LS. 51 – coupled GPCR, Adenosine A2a Lipid Res 2012; : 199 207. The role of the transcription factor 9. Huang XP, Karpiak J, Kroeze WK, receptor, is a target for new immuno- CREB in immune function. J 10 et al. Allosteric ligands for the oncology therapeutics. A second is Immunol 2010; 185: 6413–6419. pharmacologically dark receptors that GPR65 polymorphisms 4. Wirasinha RC, Vijayan D, Smith GPR68 and GPR65. Nature 2015; (genotype) will become a major factor NJ, et al. GPR65 inhibits EAE 527: 477–483. for prediction of inflammatory disease. through CD4+ T cell independent 10. Leone RD, Lo YC, Powell JD. A2aR A third is that pH will enter our mechanisms that include effects on antagonists: next generation iNKT cells. Immunol Cell Biol 2018; consciousness as a major determinant checkpoint blockade for cancer 96: 128–136. for immune responses.
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