PMID- 37066358
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230417
DP  - 2023 Apr 5
TI  - Resolvin D2-GPR18 Signaling on Myeloid Cells Limits Plaque Necrosis.
LID - 2023.04.03.535493 [pii]
LID - 10.1101/2023.04.03.535493 [doi]
AB  - INTRODUCTION/OBJECTIVE: Dysregulated inflammation-resolution programs are 
      associated with atherosclerosis progression. Inflammation-resolution is in part 
      mediated by Resolvins, including Resolvin D2 (RvD2). RvD2, which activates a 
      G-protein coupled receptor (GPCR) called GPR18, limits plaque progression. 
      Cellular targets of RvD2 are not known. APPROACH AND RESULTS: Here we developed 
      humanized GPR18 floxed ("fl/fl") and a myeloid (Lysozyme M Cre) GPR18 knockout 
      (mKO) mouse. We functionally validated this model by assessing efferocytosis in 
      bone marrow derived macrophages (BMDMs) and found that RvD2 enhanced 
      efferocytosis in the fl/fl, but not in the mKO BMDMs. We employed two different 
      models to evaluate the role of GPR18 in atherosclerosis. We first used the 
      PCSK9-gain of function approach and found increased necrosis in the plaques of 
      the mKO mice compared with fl/fl mice. Next, we performed a bone marrow transfer 
      of fl/fl or mKO bone marrow into Ldlr (-/-) recipients. For these experiments, we 
      treated each genotype with either Veh or RvD2 (25 ng/mouse, 3 times/week for 3 
      weeks). Myeloid loss of GPR18 resulted in significantly more necrosis and cleaved 
      caspase-3 (+) cells compared with fl/fl transplanted mice. RvD2 treatment 
      decreased plaques necrosis and cleaved caspase-3 (+) cells in fl/fl, but not in 
      the mKO transplanted mice. CONCLUSIONS: These results are the first to suggest a 
      causative role for endogenous RvD2 signaling on myeloid cells in limiting plaque 
      necrosis. Moreover, these results provide a mechanistic basis for RvD2 as a 
      therapy limiting plaque necrosis.
FAU - Lipscomb, Masharh
AU  - Lipscomb M
AUID- ORCID: 0000-0001-6421-1470
FAU - Walis, Sean
AU  - Walis S
FAU - Marinello, Michael
AU  - Marinello M
FAU - Mena, Hebe Agustina
AU  - Mena HA
FAU - Spite, Matthew
AU  - Spite M
AUID- ORCID: 0000-0002-8868-3648
FAU - Fredman, Gabrielle
AU  - Fredman G
AUID- ORCID: 0000-0001-9974-0962
LA  - eng
PT  - Preprint
DEP - 20230405
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10104042
EDAT- 2023/04/18 06:00
MHDA- 2023/04/18 06:01
PMCR- 2023/04/14
CRDT- 2023/04/17 04:09
PHST- 2023/04/18 06:01 [medline]
PHST- 2023/04/17 04:09 [entrez]
PHST- 2023/04/18 06:00 [pubmed]
PHST- 2023/04/14 00:00 [pmc-release]
AID - 2023.04.03.535493 [pii]
AID - 10.1101/2023.04.03.535493 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Apr 5:2023.04.03.535493. doi: 10.1101/2023.04.03.535493.