{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n G protein–coupled receptor 18 (GPR18) is emerging as a multifaceted lipid-sensing receptor that mediates diverse biological functions. Several studies have shown that GPR18 is activated by endogenous lipid mediators, such as resolvin D2 and N‐arachidonoyl glycine, and that its engagement promotes resolution of inflammation by enhancing phagocyte functions including bacterial and apoptotic cell clearance and by attenuating neutrophil infiltration, thereby protecting tissues from inflammatory injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In lymphoid cells, GPR18 activation by its ligand induces intracellular calcium mobilization, down‐regulates cyclic AMP accumulation, and triggers ERK1/2 phosphorylation, implying biased agonism that is reminiscent of cannabinoid receptor signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " Furthermore, GPR18 clusters with related receptors such as EBI2 and is considered a candidate cannabinoid receptor, a notion supported by its constitutive activity and putative ‘ionic lock’ features that are amenable to targeted drug design."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cancer models, particularly in melanoma and lung adenocarcinoma metastases, GPR18 is frequently overexpressed and exhibits constitutive signaling that promotes tumor cell survival by inhibiting apoptosis, thereby identifying it as a potential anticancer target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In the gastrointestinal tract, GPR18 expression in intraepithelial lymphocytes supports optimal mucosal immunity, as evidenced by reduced reconstitution of specific T cell subsets upon receptor deficiency."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Moreover, pharmacological activation of GPR18 has been shown to attenuate intestinal inflammation and inflammatory pain"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", while diminished expression on polymorphonuclear neutrophils correlates with worsened sepsis outcomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In neural tissues, activation of GPR18 by its endogenous ligand reduces neuronal damage in ex vivo hippocampal models, suggesting neuroprotective functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " GPR18 also appears to participate in immune regulation beyond innate responses, as emerging evidence points to its role in modulating CD8 T cell functions during immune reconstitution."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Finally, GPR18 is expressed in reproductive tissues; for instance, its localization in human spermatozoa implicates novel roles in sperm physiology, and its detection in placental tissue has been quantified using digital image analysis methods."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish GPR18 as an important regulator in inflammation resolution, immune cell homeostasis, and tumor cell survival, and they support its potential as a therapeutic target in diverse pathological conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "17"}, {"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "15"}, {"type": "fg_f", "ref": "13"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "18"}, {"type": "fg_f", "ref": "12"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nan Chiang, Jesmond Dalli, Romain A Colas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of resolvin D2 receptor mediating resolution of infections and organ protection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20150225"}], "href": "https://doi.org/10.1084/jem.20150225"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26195725"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26195725"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Aritz Lopategi, Roger Flores-Costa, Bibiana Rius, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Frontline Science: Specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/JLB.3HI0517-206RR"}], "href": "https://doi.org/10.1002/JLB.3HI0517-206RR"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29601102"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29601102"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Masashi Kohno, Hitoshi Hasegawa, Atsushi Inoue, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2006.06.175"}], "href": "https://doi.org/10.1016/j.bbrc.2006.06.175"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16844083"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16844083"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Linda Console-Bram, Eugen Brailoiu, Gabriela Cristina Brailoiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of GPR18 by cannabinoid compounds: a tale of biased agonism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Pharmacol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/bph.12746"}], "href": "https://doi.org/10.1111/bph.12746"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24762058"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24762058"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Noori Sotudeh, Paula Morales, Dow P Hurst, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Towards A Molecular Understanding of The Cannabinoid Related Orphan Receptor GPR18: A Focus on Its Constitutive Activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms20092300"}], "href": "https://doi.org/10.3390/ijms20092300"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31075933"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31075933"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Mette M Rosenkilde, Tau Benned-Jensen, Helene Andersen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M602245200"}], "href": "https://doi.org/10.1074/jbc.M602245200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16540462"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16540462"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kristine Nørregaard, Tau Benned-Jensen, Mette Marie Rosenkilde "}, {"type": "b", "children": [{"type": "t", "text": "EBI2, GPR18 and GPR17--three structurally related, but biologically distinct 7TM receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Top Med Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/1568026611109060618"}], "href": "https://doi.org/10.2174/1568026611109060618"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21261596"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21261596"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Y Qin, E M E Verdegaal, M Siderius, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Quantitative expression profiling of G-protein-coupled receptors (GPCRs) in metastatic melanoma: the constitutively active orphan GPCR GPR18 as novel drug target."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pigment Cell Melanoma Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1755-148X.2010.00781.x"}], "href": "https://doi.org/10.1111/j.1755-148X.2010.00781.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20880198"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20880198"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Deyu Zhang, Qiwei Jiang, Xiangwei Ge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RHOV promotes lung adenocarcinoma cell growth and metastasis through JNK/c-Jun pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/ijbs.59939"}], "href": "https://doi.org/10.7150/ijbs.59939"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34326698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34326698"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Xiaoming Wang, Hayakazu Sumida, Jason G Cyster "}, {"type": "b", "children": [{"type": "t", "text": "GPR18 is required for a normal CD8αα intestinal intraepithelial lymphocyte compartment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20140646"}], "href": "https://doi.org/10.1084/jem.20140646"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25348153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25348153"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Amy M Becker, Derrick J Callahan, Justin M Richner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GPR18 Controls Reconstitution of Mouse Small Intestine Intraepithelial Lymphocytes following Bone Marrow Transplantation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0133854"}], "href": "https://doi.org/10.1371/journal.pone.0133854"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26197390"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26197390"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Adam Fabisiak, Natalia Fabisiak, Anna Mokrowiecka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel selective agonist of GPR18, PSB-KK-1415 exerts potent anti-inflammatory and anti-nociceptive activities in animal models of intestinal inflammation and inflammatory pain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogastroenterol Motil (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/nmo.14003"}], "href": "https://doi.org/10.1111/nmo.14003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33058313"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33058313"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Lanqiu Zhang, Chongyang Qiu, Lei Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GPR18 expression on PMNs as biomarker for outcome in patient with sepsis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Life Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.lfs.2018.11.061"}], "href": "https://doi.org/10.1016/j.lfs.2018.11.061"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30503722"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30503722"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Urszula Grabiec, Tim Hohmann, Chalid Ghadban, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protective Effect of N-Arachidonoyl Glycine-GPR18 Signaling after Excitotoxical Lesion in Murine Organotypic Hippocampal Slice Cultures."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms20061266"}], "href": "https://doi.org/10.3390/ijms20061266"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30871175"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30871175"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Hayakazu Sumida, Jason G Cyster "}, {"type": "b", "children": [{"type": "t", "text": "G-Protein Coupled Receptor 18 Contributes to Establishment of the CD8 Effector T Cell Compartment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Immunol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fimmu.2018.00660"}], "href": "https://doi.org/10.3389/fimmu.2018.00660"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29670628"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29670628"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Ashley L Hein, Maheswari Mukherjee, Geoffrey A Talmon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "QuPath Digital Immunohistochemical Analysis of Placental Tissue."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pathol Inform (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4103/jpi.jpi_11_21"}], "href": "https://doi.org/10.4103/jpi.jpi_11_21"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34881095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34881095"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "János Haskó, Csilla Fazakas, Judit Molnár, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CB2 receptor activation inhibits melanoma cell transmigration through the blood-brain barrier."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms15058063"}], "href": "https://doi.org/10.3390/ijms15058063"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24815068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24815068"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Lian Yu, Shuhui Cao, Jingwen Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prognostic value and immune infiltration of a novel stromal/immune score-related P2RY12 in lung adenocarcinoma microenvironment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Immunopharmacol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.intimp.2021.107734"}], "href": "https://doi.org/10.1016/j.intimp.2021.107734"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34175738"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34175738"}]}]}]}