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Myeloid RVD2-GPR18 Signaling Axis Li...

Lipscomb, Masharh J.,

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Myeloid RVD2-GPR18 Signaling Axis Limits Plaque Necrosis and Senescent Macrophages in Atherosclerosis /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Myeloid RVD2-GPR18 Signaling Axis Limits Plaque Necrosis and Senescent Macrophages in Atherosclerosis // Masharh J Lipscomb.
Author:	Lipscomb, Masharh J.,
Description:	1 electronic resource (146 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-10, Section: B.
Contained By:	Dissertations Abstracts International85-10B.
Subject:	Physiology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31146506
ISBN:	9798382216430

Myeloid RVD2-GPR18 Signaling Axis Limits Plaque Necrosis and Senescent Macrophages in Atherosclerosis /
Lipscomb, Masharh J.,

Myeloid RVD2-GPR18 Signaling Axis Limits Plaque Necrosis and Senescent Macrophages in Atherosclerosis /Masharh J Lipscomb. - 1 electronic resource (146 pages)

Source: Dissertations Abstracts International, Volume: 85-10, Section: B.

Background Dysregulated inflammation-resolution programs are associated with atherosclerosis progression and results over the past decade has revealed a protective role for resolvins, like Resolvin D2 (RvD2) in reducing atherosclerosis progression in animal models. Mechanisms associated with this protection are an active area of research. Senescent cells (SCs), which accumulate in atherosclerotic plaques, have been shown to worsen atherosclerosis by driving necrosis. Here, we investigate the role of endogenous RvD2-GPR18 signaling in atherosclerosis and we question whether RvD2 promotes the clearance of senescent cells in plaques.Methods and Results: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. To understand RvD2- GPR18 signaling in atherosclerosis, we performed a bone marrow transfer of fl/fl or mKO bone marrow into Ldlr-/- recipients. To understand RvD2-GPR18 signaling in atherosclerosis, 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 Vehicle/PBS or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis, accumulation of cleaved caspase-3+ positive cells and decreased the percentage of Arginase-1+ -Mac2+ cells without a change in overall Mac2+ plaque macrophages, compared with fl/fl→Ldlr-/- transplanted mice. RvD2 treatment decreased plaque necrosis, the percent cleaved caspase-3 + cells and increased the percent of Arginase-1+ -Mac2+ cells in fl/fl→Ldlr-/- mice, but not in the mKO→Ldlr-/- transplanted mice. We then investigated whether senescent macrophages (SC-macs) could be cleared by efferocytosis. We observed that SC-macs were not as readily efferocytozed as apoptotic cells, in part through elevated expression of key "Don't eat me" signals called CD47 and CD24. Knockdown of CD24 or blockade or CD47 significantly improved SC uptake by macrophages, which suggests that these receptors served as an impediment to engulfment. Next, we used the tri-modal p16- 3MR mouse model to investigate whether genetic removal of hematopoietic SCs during advanced atherosclerosis reduced these "don't' eat me" signals on plaque macrophages. Removal of p16+ hematopoietic cells in advanced atherosclerotic plaques revealed a decrease in the percent of CD68+CD24+ and CD68+CD47+ cells, which was associated with increased plaque remodeling. Next, we examined whether RvD2-GPR18 signaling limited SC-macs in plaques. We found that atherosclerotic mice lacking myeloid GPR18 had increased necrosis, less fibrous caps and increased CD68+CD24+ and CD68+CD47+ cells. Finally, treatment of Ldlr-/- mice with Veh or RvD2 (50 ng/mouse, 3 times/wk for 3 wks) resulted in less necrosis, improved fibrous caps, decreased percentage of CD68+CD24+ and CD68+CD47+ cells. In vitro experiments revealed that RvD2 treatment increased efferocytosis of SC-macs, suggesting that RvD2 enhanced the clearance of these cells in plaques.Conclusions: These results suggest that CD24 and CD47 limit SC-mac clearance. Moreover, this work highlights a causative role for endogenous RvD2 signaling on myeloid cells in limiting SC accumulation in advanced murine plaques and suggest that RvD2 may limit necrosis through removal of senescent cells.

English

ISBN: 9798382216430Subjects--Topical Terms:

518431
Physiology.
Subjects--Index Terms:

GPR18

Myeloid RVD2-GPR18 Signaling Axis Limits Plaque Necrosis and Senescent Macrophages in Atherosclerosis /
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245 1 0 $a Myeloid RVD2-GPR18 Signaling Axis Limits Plaque Necrosis and Senescent Macrophages in Atherosclerosis / $c Masharh J Lipscomb.
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500 $a Source: Dissertations Abstracts International, Volume: 85-10, Section: B.
500 $a Advisors: Fredman, Gabrielle Committee members: Jourd'heuil, David; Zuloaga, Kristen; Adam, Alejandro P.; de Noronha, Carlos M.; MacNamara, Katherine.
502 $b Ph.D. $c Albany Medical College $d 2024.
520 $a Background Dysregulated inflammation-resolution programs are associated with atherosclerosis progression and results over the past decade has revealed a protective role for resolvins, like Resolvin D2 (RvD2) in reducing atherosclerosis progression in animal models. Mechanisms associated with this protection are an active area of research. Senescent cells (SCs), which accumulate in atherosclerotic plaques, have been shown to worsen atherosclerosis by driving necrosis. Here, we investigate the role of endogenous RvD2-GPR18 signaling in atherosclerosis and we question whether RvD2 promotes the clearance of senescent cells in plaques.Methods and Results: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. To understand RvD2- GPR18 signaling in atherosclerosis, we performed a bone marrow transfer of fl/fl or mKO bone marrow into Ldlr-/- recipients. To understand RvD2-GPR18 signaling in atherosclerosis, 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 Vehicle/PBS or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis, accumulation of cleaved caspase-3+ positive cells and decreased the percentage of Arginase-1+ -Mac2+ cells without a change in overall Mac2+ plaque macrophages, compared with fl/fl→Ldlr-/- transplanted mice. RvD2 treatment decreased plaque necrosis, the percent cleaved caspase-3 + cells and increased the percent of Arginase-1+ -Mac2+ cells in fl/fl→Ldlr-/- mice, but not in the mKO→Ldlr-/- transplanted mice. We then investigated whether senescent macrophages (SC-macs) could be cleared by efferocytosis. We observed that SC-macs were not as readily efferocytozed as apoptotic cells, in part through elevated expression of key "Don't eat me" signals called CD47 and CD24. Knockdown of CD24 or blockade or CD47 significantly improved SC uptake by macrophages, which suggests that these receptors served as an impediment to engulfment. Next, we used the tri-modal p16- 3MR mouse model to investigate whether genetic removal of hematopoietic SCs during advanced atherosclerosis reduced these "don't' eat me" signals on plaque macrophages. Removal of p16+ hematopoietic cells in advanced atherosclerotic plaques revealed a decrease in the percent of CD68+CD24+ and CD68+CD47+ cells, which was associated with increased plaque remodeling. Next, we examined whether RvD2-GPR18 signaling limited SC-macs in plaques. We found that atherosclerotic mice lacking myeloid GPR18 had increased necrosis, less fibrous caps and increased CD68+CD24+ and CD68+CD47+ cells. Finally, treatment of Ldlr-/- mice with Veh or RvD2 (50 ng/mouse, 3 times/wk for 3 wks) resulted in less necrosis, improved fibrous caps, decreased percentage of CD68+CD24+ and CD68+CD47+ cells. In vitro experiments revealed that RvD2 treatment increased efferocytosis of SC-macs, suggesting that RvD2 enhanced the clearance of these cells in plaques.Conclusions: These results suggest that CD24 and CD47 limit SC-mac clearance. Moreover, this work highlights a causative role for endogenous RvD2 signaling on myeloid cells in limiting SC accumulation in advanced murine plaques and suggest that RvD2 may limit necrosis through removal of senescent cells.
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650 4 $a Biology. $3 522710
650 4 $a Cellular biology. $3 3172791
653 $a GPR18
653 $a Inflammation
653 $a Resolution
653 $a Resolvin D2
653 $a Senescence
690 $a 0719
690 $a 0306
690 $a 0379
710 2 $a Albany Medical College. $b Molecular and Cellular Physiology (MCP). $e degree granting institution. $3 3819063
720 1 $a Fredman, Gabrielle $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 85-10B.
790 $a 0362
791 $a Ph.D.
792 $a 2024
856 4 0 $u https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31146506