Id |
Subject |
Object |
Predicate |
Lexical cue |
T125 |
0-14 |
Sentence |
denotes |
SPMs receptors |
T126 |
15-78 |
Sentence |
denotes |
Herein, we briefly describe each known SPMs receptors (Fig. 2). |
T127 |
79-303 |
Sentence |
denotes |
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. |
T128 |
304-506 |
Sentence |
denotes |
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. |
T129 |
507-540 |
Sentence |
denotes |
2005, 2007; Krishnamoorthy et al. |
T130 |
541-547 |
Sentence |
denotes |
2010). |
T131 |
548-716 |
Sentence |
denotes |
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. |
T132 |
717-732 |
Sentence |
denotes |
2020; Im 2012). |
T133 |
734-753 |
Sentence |
denotes |
Chemerin receptor 1 |
T134 |
754-945 |
Sentence |
denotes |
Chemerin 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. |
T135 |
946-1032 |
Sentence |
denotes |
Besides, ERV1 has been identified in adipocytes and endothelial cells (Luangsay et al. |
T136 |
1033-1039 |
Sentence |
denotes |
2009). |
T137 |
1040-1146 |
Sentence |
denotes |
ERV1 was initially classified as an orphan GPCR with homology to the formyl peptide receptor (Gantz et al. |
T138 |
1147-1211 |
Sentence |
denotes |
1996) and the anaphylatoxin C3a and C5a receptors (Samson et al. |
T139 |
1212-1323 |
Sentence |
denotes |
1998) until recently when it was discovered to be a receptor for the chemotactic protein chemerin (Meder et al. |
T140 |
1324-1330 |
Sentence |
denotes |
2003). |
T141 |
1331-1471 |
Sentence |
denotes |
In addition to chemerin, RvE1 was identified as a second endogenous agonist through a screening program against the GPCR panel (Arita et al. |
T142 |
1472-1478 |
Sentence |
denotes |
2007). |
T143 |
1479-1647 |
Sentence |
denotes |
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. |
T144 |
1648-1669 |
Sentence |
denotes |
2005; Wittamer et al. |
T145 |
1670-1676 |
Sentence |
denotes |
2004). |
T146 |
1677-1832 |
Sentence |
denotes |
ERV1 overexpressing mice showed a large increase in phagocytosis upon decreased neutrophil inhibition and decreased neutrophil infiltration (Herrera et al. |
T147 |
1833-1839 |
Sentence |
denotes |
2015). |
T148 |
1840-1942 |
Sentence |
denotes |
Also, RvE2 is a partial agonist compared to RvE1 in CHO-chemerin1 β-arrestin recruitment (Isobe et al. |
T149 |
1943-1950 |
Sentence |
denotes |
2012a). |
T150 |
1951-2086 |
Sentence |
denotes |
However, since there is no additional information on this ligand, further investigation of potential ligand-receptor pairs is required. |
T151 |
2088-2141 |
Sentence |
denotes |
N-formyl peptide receptor 2/LX A4 receptor (FPR2/ALX) |
T152 |
2142-2297 |
Sentence |
denotes |
Originally 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. |
T153 |
2298-2304 |
Sentence |
denotes |
1992). |
T154 |
2305-2543 |
Sentence |
denotes |
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. |
T155 |
2544-2562 |
Sentence |
denotes |
1994; Brink et al. |
T156 |
2563-2569 |
Sentence |
denotes |
2003). |
T157 |
2570-2696 |
Sentence |
denotes |
Binding of LXA4 leads to the stimulation of monocyte chemotaxis, macrophage differentiation, and efferocytosis (Maderna et al. |
T158 |
2697-2727 |
Sentence |
denotes |
2010; Maddox and Serhan 1996). |
T159 |
2728-2852 |
Sentence |
denotes |
LXA4 also reduces the adaptive immune response by reducing memory B cell antibody production and proliferation (Ramon et al. |
T160 |
2853-2859 |
Sentence |
denotes |
2014). |
T161 |
2860-3030 |
Sentence |
denotes |
Endogenous 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. |
T162 |
3031-3050 |
Sentence |
denotes |
1997; Cooray et al. |
T163 |
3051-3057 |
Sentence |
denotes |
2013). |
T164 |
3058-3217 |
Sentence |
denotes |
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. |
T165 |
3218-3357 |
Sentence |
denotes |
On the other hand, endogenous antagonists, including serum amyloid A (SAA) and cathelicidin (LL-37) have been identified (Bozinovski et al. |
T166 |
3358-3374 |
Sentence |
denotes |
2012; Wan et al. |
T167 |
3375-3381 |
Sentence |
denotes |
2011). |
T168 |
3383-3388 |
Sentence |
denotes |
GPR18 |
T169 |
3389-3487 |
Sentence |
denotes |
GPR18 was discovered as a receptor for RvD2 through GPCR-β-arrestin-based screening (Chiang et al. |
T170 |
3488-3556 |
Sentence |
denotes |
2015), and the receptor was referred to as DRV2/GPR18 (Chiang et al. |
T171 |
3557-3570 |
Sentence |
denotes |
2017, 2019a). |
T172 |
3571-3622 |
Sentence |
denotes |
Besides, several other ligands activate DRV2/GPR18. |
T173 |
3623-3938 |
Sentence |
denotes |
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. |
T174 |
3939-3957 |
Sentence |
denotes |
2003; Kohno et al. |
T175 |
3958-3964 |
Sentence |
denotes |
2006). |
T176 |
3965-4042 |
Sentence |
denotes |
GPR18 is abundantly expressed in PMNs, monocytes and macrophages (Wang et al. |
T177 |
4043-4049 |
Sentence |
denotes |
2014). |
T178 |
4050-4416 |
Sentence |
denotes |
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). |
T179 |
4417-4680 |
Sentence |
denotes |
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). |
T180 |
4682-4687 |
Sentence |
denotes |
GPR32 |
T181 |
4688-4814 |
Sentence |
denotes |
GPR32 is primarily expressed in human PMN, monocytes, adipose tissue and vascular endothelial cells (Sansbury and Spite 2016). |
T182 |
4815-5043 |
Sentence |
denotes |
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. |
T183 |
5044-5050 |
Sentence |
denotes |
2010). |
T184 |
5051-5187 |
Sentence |
denotes |
Although RvD1 has a higher affinity for GPR32 than FPR2/ALX, its interaction with GPR32 has not been extensively studied (Norling et al. |
T185 |
5188-5194 |
Sentence |
denotes |
2012). |
T186 |
5195-5310 |
Sentence |
denotes |
This could be since GPR32 exists as a pseudogene in rodents, which makes animal testing in principle inappropriate. |
T187 |
5311-5505 |
Sentence |
denotes |
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. |
T188 |
5506-5512 |
Sentence |
denotes |
2016). |
T189 |
5513-5637 |
Sentence |
denotes |
Also, GPR32 was also involved when during the inhibition of the EMT phenomenon of lung cancer cell lines by RvD1 (Lee et al. |
T190 |
5638-5644 |
Sentence |
denotes |
2013). |
T191 |
5645-5784 |
Sentence |
denotes |
Additionally, RvD3, AT-RvD3, and RvD5 have all been shown to activate GPR32 in a recombinant system of β-arrestin recruitment (Dalli et al. |
T192 |
5785-5805 |
Sentence |
denotes |
2013b; Chiang et al. |
T193 |
5806-5812 |
Sentence |
denotes |
2012). |
T194 |
5813-5885 |
Sentence |
denotes |
These facts suggest the potential redundancy of ligands acting on GPCRs. |
T195 |
5887-5892 |
Sentence |
denotes |
GPR37 |
T196 |
5893-6063 |
Sentence |
denotes |
GPR37 or Parkin-related endothelin-like receptor (Pael-R) was originally discovered through genomic library screening to find new neuropeptide receptors (Marazziti et al. |
T197 |
6064-6070 |
Sentence |
denotes |
1997). |
T198 |
6071-6221 |
Sentence |
denotes |
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. |
T199 |
6222-6228 |
Sentence |
denotes |
2015). |
T200 |
6229-6382 |
Sentence |
denotes |
Mutations within GPR37 affect various autism spectrum disorders, regulation of dopamine reuptake and oligodendrocyte differentiation (Fujita-Jimbo et al. |
T201 |
6383-6405 |
Sentence |
denotes |
2012; Marazziti et al. |
T202 |
6406-6423 |
Sentence |
denotes |
2007; Yang et al. |
T203 |
6424-6430 |
Sentence |
denotes |
2016). |
T204 |
6431-6629 |
Sentence |
denotes |
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. |
T205 |
6630-6636 |
Sentence |
denotes |
2018). |
T206 |
6637-6869 |
Sentence |
denotes |
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). |
T207 |
6870-7086 |
Sentence |
denotes |
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. |
T208 |
7088-7104 |
Sentence |
denotes |
Leukotriene BLT1 |
T209 |
7105-7361 |
Sentence |
denotes |
BLT1 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. |
T210 |
7362-7380 |
Sentence |
denotes |
1997; Arita et al. |
T211 |
7381-7387 |
Sentence |
denotes |
2007). |
T212 |
7388-7606 |
Sentence |
denotes |
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. |
T213 |
7607-7613 |
Sentence |
denotes |
2007). |
T214 |
7614-7796 |
Sentence |
denotes |
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. |
T215 |
7797-7996 |
Sentence |
denotes |
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. |
T216 |
7997-8003 |
Sentence |
denotes |
2007). |
T217 |
8004-8208 |
Sentence |
denotes |
Activation 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. |
T218 |
8209-8215 |
Sentence |
denotes |
2008). |
T219 |
8216-8434 |
Sentence |
denotes |
RvE2 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. |
T220 |
8435-8441 |
Sentence |
denotes |
2012). |
T221 |
8442-8570 |
Sentence |
denotes |
Various pro-resolving roles of RvE2 have been proposed, including regulation of PMN infiltration and IL-10 production (Oh et al. |
T222 |
8571-8577 |
Sentence |
denotes |
2012). |
T223 |
8578-8716 |
Sentence |
denotes |
However, while RvE1 promotes NADPH oxidase-mediated ROS production through the BLT1, RvE2 and RvE3 do not exhibit this effect (Unno et al. |
T224 |
8717-8723 |
Sentence |
denotes |
2018). |
T225 |
8725-8762 |
Sentence |
denotes |
Activation of other receptors by SPMs |
T226 |
8763-8833 |
Sentence |
denotes |
A few studies have reported the possibility of other GPCR involvement. |
T227 |
8834-8942 |
Sentence |
denotes |
Among them, GPR101 mediates the pro-resolving effects of RvD5n-3 DPA in arthritis and infection (Flak et al. |
T228 |
8943-8949 |
Sentence |
denotes |
2020). |
T229 |
8950-9042 |
Sentence |
denotes |
Besides, SPMs have been reported to activate non-GPCRs receptors, such as nuclear receptors. |
T230 |
9043-9229 |
Sentence |
denotes |
In 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. |
T231 |
9230-9236 |
Sentence |
denotes |
2011). |
T232 |
9237-9354 |
Sentence |
denotes |
This suggests that PD1 is capable of enhancing the peroxisome proliferator-activated receptor gamma (PPARγ) (Fig. 2). |
T233 |
9355-9453 |
Sentence |
denotes |
The transcriptional activity of PPARγ was significantly increased after treatment with 100 nM PD1. |
T234 |
9454-9685 |
Sentence |
denotes |
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. |
T235 |
9686-9692 |
Sentence |
denotes |
2012). |
T236 |
9693-9808 |
Sentence |
denotes |
Recently, it has been reported that LXA4 binds to the nuclear aryl hydrocarbon receptor (AhR) (Fig. 2) (Asha et al. |
T237 |
9809-9815 |
Sentence |
denotes |
2020). |
T238 |
9816-9878 |
Sentence |
denotes |
A GPCR that acts directly on MaR1 has not yet been identified. |
T239 |
9879-10201 |
Sentence |
denotes |
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. |
T240 |
10202-10345 |
Sentence |
denotes |
2019b), which initiates cAMP, impedance changes, and stimulate an innate immune response against PMNs, monocytes and macrophages (Chiang et al. |
T241 |
10346-10353 |
Sentence |
denotes |
2019b). |