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{"project":"LitCovid-PD-HP","denotations":[{"id":"T11","span":{"begin":5595,"end":5606},"obj":"Phenotype"},{"id":"T12","span":{"begin":6201,"end":6207},"obj":"Phenotype"},{"id":"T13","span":{"begin":6267,"end":6292},"obj":"Phenotype"},{"id":"T14","span":{"begin":6830,"end":6845},"obj":"Phenotype"},{"id":"T15","span":{"begin":8906,"end":8915},"obj":"Phenotype"}],"attributes":[{"id":"A11","pred":"hp_id","subj":"T11","obj":"http://purl.obolibrary.org/obo/HP_0100526"},{"id":"A12","pred":"hp_id","subj":"T12","obj":"http://purl.obolibrary.org/obo/HP_0000717"},{"id":"A13","pred":"hp_id","subj":"T13","obj":"http://purl.obolibrary.org/obo/HP_0000729"},{"id":"A14","pred":"hp_id","subj":"T14","obj":"http://purl.obolibrary.org/obo/HP_0002140"},{"id":"A15","pred":"hp_id","subj":"T15","obj":"http://purl.obolibrary.org/obo/HP_0001369"}],"text":"SPMs receptors\nHerein, we briefly describe each known SPMs receptors (Fig. 2). Previous studies have demonstrated that pro-resolving activities of SPMs occur through activation of one or more G protein-coupled receptors (GPCRs), suitable receptors for several types of SPMs have not yet been identified. Four GPCRs have been reported as receptors for RvD1 and RvE1; however, it has not been determined whether other Rvs and PDs such as RvE2, RvE4, RvD2, RvD3, PDs, and MaRs act on these GPCRs (Arita et al. 2005, 2007; Krishnamoorthy et al. 2010). For recent and specific physiological actions of these receptors and research data in KO mice, we would like to refer to other reviews and references there (Park et al. 2020; Im 2012).\n\nChemerin receptor 1\nChemerin receptor 1 (chemerin1, ChemR23, or ERV1) is expressed on a wide range of immune cells, including monocytes, macrophages, natural killer cells, bone marrow cells, and dendritic cells. Besides, ERV1 has been identified in adipocytes and endothelial cells (Luangsay et al. 2009). ERV1 was initially classified as an orphan GPCR with homology to the formyl peptide receptor (Gantz et al. 1996) and the anaphylatoxin C3a and C5a receptors (Samson et al. 1998) until recently when it was discovered to be a receptor for the chemotactic protein chemerin (Meder et al. 2003).\nIn addition to chemerin, RvE1 was identified as a second endogenous agonist through a screening program against the GPCR panel (Arita et al. 2007). ERV1 (chemokine like receptor 1, also known as CMKLR1) is a receptor for RvE1, which has been shown to bind more strongly than chemerin (a peptide ligand) (Arita et al. 2005; Wittamer et al. 2004). ERV1 overexpressing mice showed a large increase in phagocytosis upon decreased neutrophil inhibition and decreased neutrophil infiltration (Herrera et al. 2015). Also, RvE2 is a partial agonist compared to RvE1 in CHO-chemerin1 β-arrestin recruitment (Isobe et al. 2012a). However, since there is no additional information on this ligand, further investigation of potential ligand-receptor pairs is required.\n\nN-formyl peptide receptor 2/LX A4 receptor (FPR2/ALX)\nOriginally FPR2 was classified as an FPR receptor due to its activation by the low-affinity endogenous agonist N-formyl methionyl peptide (fMLP) (Ye et al. 1992). The receptor was reclassified as FPR2/ALX, as LXA4 exhibited the highest affinity of all FPR2/ALX endogenous agonists through screening of various receptor ligands using radiolabelled [3H]-LXA4 and subsequent GTPase activity (Fiore et al. 1994; Brink et al. 2003). Binding of LXA4 leads to the stimulation of monocyte chemotaxis, macrophage differentiation, and efferocytosis (Maderna et al. 2010; Maddox and Serhan 1996). LXA4 also reduces the adaptive immune response by reducing memory B cell antibody production and proliferation (Ramon et al. 2014).\nEndogenous and exogenous lipids, peptides, and proteins have been shown to bind and activate FPR2/ALX to produce inflammatory and anti-inflammatory effects (Takano et al. 1997; Cooray et al. 2013). Both the LXs and Rvs families, including LXA4, AT-LXA4 (15-epi-LXA4), RvD1, AT-RvD1 (17-epi-RvD1), and Annexin A1 (ANXA1) activate receptors with high potency. On the other hand, endogenous antagonists, including serum amyloid A (SAA) and cathelicidin (LL-37) have been identified (Bozinovski et al. 2012; Wan et al. 2011).\n\nGPR18\nGPR18 was discovered as a receptor for RvD2 through GPCR-β-arrestin-based screening (Chiang et al. 2015), and the receptor was referred to as DRV2/GPR18 (Chiang et al. 2017, 2019a). Besides, several other ligands activate DRV2/GPR18. These include endogenous ligands such as N-arachidonylglycine (NAGly), anandamide, a metabolite of the endocannabinoid anandamide, synthetic ligands such as abnormal-cannabidiol (Abn-CBD), and O-1918, a partial agonist, which can be used as a pharmacological tool to inhibit DRV2/GPR18 signalling (Offertaler et al. 2003; Kohno et al. 2006). GPR18 is abundantly expressed in PMNs, monocytes and macrophages (Wang et al. 2014). In addition to the resolution of inflammation, while GPR18 has low structural similarity to the cannabinoid receptors CB1, CB2, and GPR55, it responds to endogenous and synthetic cannabinoid ligands including n-arachidonoyl ethanolamine (AEA), 2-arachidonoyl glycerol (2-AG), Δ9-tetrahydrocannabinol (Δ9-THC), and, arachidonoylcyclopropylamide (ACPA) (McHugh, 2012). Also interestingly, GPR18 is structurally very similar to EBV-induced receptor 2 (EBI2), whose expression is increased more than 20 times in Epstein-Barr virus (EBV) infected cells, and is a GPCR receptor clustered together in the 13q32 (Rosenkilde et al., 2006).\n\nGPR32\nGPR32 is primarily expressed in human PMN, monocytes, adipose tissue and vascular endothelial cells (Sansbury and Spite 2016). RvD1 was identified as a potential agonist due to the activation of GPR32, where [3H]-RvD1 binds to human leukocytes and significantly lowers TNF-α-stimulated NF-κB signalling in GPR32 overexpressing cells (Krishnamoorthy et al. 2010). Although RvD1 has a higher affinity for GPR32 than FPR2/ALX, its interaction with GPR32 has not been extensively studied (Norling et al. 2012). This could be since GPR32 exists as a pseudogene in rodents, which makes animal testing in principle inappropriate. Treatment of inflammatory macrophages expressing GPR32 with RvD1 enhanced the pro-resolving phenotype to increase phagocytosis and decrease the secretion of inflammatory cytokines (Schmid et al. 2016). Also, GPR32 was also involved when during the inhibition of the EMT phenomenon of lung cancer cell lines by RvD1 (Lee et al. 2013). Additionally, RvD3, AT-RvD3, and RvD5 have all been shown to activate GPR32 in a recombinant system of β-arrestin recruitment (Dalli et al. 2013b; Chiang et al. 2012). These facts suggest the potential redundancy of ligands acting on GPCRs.\n\nGPR37\nGPR37 or Parkin-related endothelin-like receptor (Pael-R) was originally discovered through genomic library screening to find new neuropeptide receptors (Marazziti et al. 1997). The GPR37 receptor is primarily expressed in the brain and is associated with neurological disorders such as Parkin’s disease and autism (Lopes et al. 2015). Mutations within GPR37 affect various autism spectrum disorders, regulation of dopamine reuptake and oligodendrocyte differentiation (Fujita-Jimbo et al. 2012; Marazziti et al. 2007; Yang et al. 2016). PD1 is considered as a ligand for GPR37 because it induced a significant increase in intracellular calcium in HEK293 cells overexpressing GPR37 and murine peritoneal-derived macrophages (Bang et al. 2018). Based on the fact that Gpr37-/- mice exhibited increased apoptosis and infarct size, it has recently been suggested that GPR37 is also involved in cell damage protection and inflammation after ischemic stroke (McCrary et al., 2019). However, due to its clear role in the central nervous system (CNS), the development of a therapeutic agent targeting GPR37 requires a balance between the effect on the central nervous system and therapeutic benefits.\n\nLeukotriene BLT1\nBLT1 has also been shown to be a receptor for RvE1 although its clone, high-affinity leukotriene B4 (LTB4) is a potent lipid inflammatory chemoattractant, inducing T helper cell chemotaxis and early effector T cell recruitment through BLT1 (Yokomizo et al. 1997; Arita et al. 2007). BLT1 shares 21% sequence identity with chemerin1; while this value is relatively low, selective BLT1 antagonist U-75,302 has been demonstrated to replace the binding of [3H]-RvE1 to the human PMN membrane (Arita et al. 2007). Besides, although RvE1 is 100 times less potent than LTB4, it inhibited adenylate cyclase activity and induced intracellular calcium mobilization in HEK293 cells overexpressing BLT1. These data indicate the role of RvE1 in reducing BLT1-induced inflammation by RvE1 acting as a partial agonist that competes with LTB4-mediated NF-κB activation and calcium mobilization (Arita et al. 2007).\nActivation of BLT1 by RvE1 also serves as a feedback mechanism for other SPMs, including increased production of LXA4 in the FPR2/ALX-mediated resolution of allergic pulmonary inflammation (Haworth et al. 2008).\nRvE2 was identified as an additional BLT1 agonist, and the β-arrestin assay showed that RvE2 blocked LTB4-mediated β-arrestin signalling with similar efficacy to RvE1, indicating direct competition with LTB4 (Oh et al. 2012). Various pro-resolving roles of RvE2 have been proposed, including regulation of PMN infiltration and IL-10 production (Oh et al. 2012). However, while RvE1 promotes NADPH oxidase-mediated ROS production through the BLT1, RvE2 and RvE3 do not exhibit this effect (Unno et al. 2018).\n\nActivation of other receptors by SPMs\nA few studies have reported the possibility of other GPCR involvement. Among them, GPR101 mediates the pro-resolving effects of RvD5n-3 DPA in arthritis and infection (Flak et al. 2020). Besides, SPMs have been reported to activate non-GPCRs receptors, such as nuclear receptors.\nIn a dose-dependent manner, PD1 enhances PPARγ transcriptional activation reporter activity in human neuron-glia (HNG) cells co-transfected with hPPARγ-GAL4 and MH100-tk-Luc (Zhao et al. 2011). This suggests that PD1 is capable of enhancing the peroxisome proliferator-activated receptor gamma (PPARγ) (Fig. 2). The transcriptional activity of PPARγ was significantly increased after treatment with 100 nM PD1. RvD1 was also assumed to be a ligand for PPARγ and inhibited IκBα degradation and NF-κB p65 nuclear translocation in an LPS-induced lung injury model, which was partially reversed by the PPARγ inhibitor GW9662 (Fig. 2) (Liao et al. 2012). Recently, it has been reported that LXA4 binds to the nuclear aryl hydrocarbon receptor (AhR) (Fig. 2) (Asha et al. 2020).\nA GPCR that acts directly on MaR1 has not yet been identified. However, MaR1 blocks TRPV1-mediated currents in neurons, acts as a ligand for the retinoid-associated orphan receptor α (RORα), and inhibits TLR4 signalling (Fig. 2) (Park 2015), Chiang et al. found that MaR1 can activate LGR6, a member of the glycoprotein hormone receptor subfamily of rhodopsin-like GPCRs (Chiang et al. 2019b), which initiates cAMP, impedance changes, and stimulate an innate immune response against PMNs, monocytes and macrophages (Chiang et al. 2019b)."}

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