Dataset Information

Identification of Chemotype Agonists for Human Resolvin D1 Receptor DRV1 with Pro-Resolving Functions.

ABSTRACT: Resolution of acute inflammation is governed, in part, by specialized pro-resolving mediators, including lipoxins, resolvins, protectins, and maresins. Among them, resolvin D1 (RvD1) exhibits potent pro-resolving functions via activating human resolvin D1 receptor (DRV1/GPR32). RvD1 is a complex molecule that requires challenging organic synthesis, diminishing its potential as a therapeutic. Therefore, we implemented a high-throughput screening of small-molecule libraries and identified several chemotypes that activated recombinant DRV1, represented by NCGC00120943 (C1A), NCGC00135472 (C2A), pMPPF, and pMPPI. These chemotypes also elicited rapid impedance changes in cells overexpressing recombinant DRV1. With human macrophages, they each stimulated phagocytosis of serum-treated zymosan at concentrations comparable with that of RvD1, the endogenous DRV1 ligand. In addition, macrophage phagocytosis of live E. coli was significantly increased by these chemotypes in DRV1-transfected macrophages, compared with mock-transfected cells. Taken together, these chemotypes identified by unbiased screens act as RvD1 mimetics, exhibiting pro-resolving functions via interacting with human DRV1.

SUBMITTER: Chiang N

PROVIDER: S-EPMC6405215 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Identification of Chemotype Agonists for Human Resolvin D1 Receptor DRV1 with Pro-Resolving Functions.

Chiang Nan N Barnaeva Elena E Hu Xin X Marugan Juan J Southall Noel N Ferrer Marc M Serhan Charles N CN

Cell chemical biology 20181213 2

Resolution of acute inflammation is governed, in part, by specialized pro-resolving mediators, including lipoxins, resolvins, protectins, and maresins. Among them, resolvin D1 (RvD1) exhibits potent pro-resolving functions via activating human resolvin D1 receptor (DRV1/GPR32). RvD1 is a complex molecule that requires challenging organic synthesis, diminishing its potential as a therapeutic. Therefore, we implemented a high-throughput screening of small-molecule libraries and identified several ...[more]

PMID: 30554914

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Project description:BackgroundEarly brain injury (EBI) has been thought to be a key factor affecting the prognosis of subarachnoid hemorrhage (SAH). Many pathologies are involved in EBI, with inflammation and neuronal death being crucial to this process. Resolvin D1 (RvD1) has shown superior anti-inflammatory properties by interacting with lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) in various diseases. However, it remains not well described about its role in the central nervous system (CNS). Thus, the goal of the present study was to elucidate the potential functions of the RvD1-ALX/FPR2 interaction in the brain after SAH.MethodsWe used an in vivo model of endovascular perforation and an in vitro model of hemoglobin (Hb) exposure as SAH models in the current study. RvD1 was used at a concentration of 25 nM in our experiments. Western blotting, quantitative polymerase chain reaction (qPCR), immunofluorescence, and other chemical-based assays were performed to assess the cellular localizations and time course fluctuations in ALX/FPR2 expression, evaluate the effects of RvD1 on Hb-induced primary microglial activation and neuronal damage, and confirm the role of ALX/FPR2 in the function of RvD1.ResultsALX/FPR2 was expressed on both microglia and neurons, but not astrocytes. RvD1 exerted a good inhibitory effect in the microglial pro-inflammatory response induced by Hb, possibly by regulating the IRAK1/TRAF6/NF-κB or MAPK signaling pathways. RvD1 could also potentially attenuate Hb-induced neuronal oxidative damage and apoptosis. Finally, the mRNA expression of IRAK1/TRAF6 in microglia and GPx1/bcl-xL in neurons was reversed by the ALX/FPR2-specific antagonist Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRW4), indicating that ALX/FPR2 could mediate the neuroprotective effects of RvD1.ConclusionsThe results of the present study indicated that the RvD1-ALX/FPR2 interaction could potentially play dual roles in the CNS, as inhibiting Hb promoted microglial pro-inflammatory polarization and ameliorating Hb induced neuronal oxidant damage and death. These results shed light on a good therapeutic target (ALX/FPR2) and a potential effective drug (RvD1) for the treatment of SAH and other inflammation-associated brain diseases.

Dataset Information

Identification of Chemotype Agonists for Human Resolvin D1 Receptor DRV1 with Pro-Resolving Functions.

Publications

Identification of Chemotype Agonists for Human Resolvin D1 Receptor DRV1 with Pro-Resolving Functions.

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