Dataset Information

Resolvin D1 promotes efferocytosis in aging by limiting senescent cell-induced MerTK cleavage.

ABSTRACT: Inflammation-resolution is mediated by the balance between specialized pro-resolving mediators (SPMs) like resolvin D1 (RvD1) and pro-inflammatory factors, like leukotriene B₄ (LTB₄). A key cellular process of inflammation-resolution is efferocytosis. Aging is associated with defective inflammation-resolution and the accumulation of pro-inflammatory senescent cells (SCs). Therefore, understanding mechanism(s) that underpin this impairment is a critical gap. Here, using a model of hind limb ischemia-reperfusion (I/R) remote lung injury, we present evidence that aging is associated with heightened inflammation, impaired SPM:LT ratio, defective efferocytosis, and a decrease in MerTK levels in injured lungs. Treatment with RvD1 mitigated I/R lung injury in aging, promoted efferocytosis, and prevented the decrease of MerTK in injured lungs from old mice. Old MerTK cleavage-resistant mice (MerTK^CR) exhibited less neutrophils or polymorpho nuclear cells infiltration and had improved efferocytosis compared with old WT controls. Mechanistically, macrophages that were treated with conditioned media (CM) from senescent cells had increased MerTK cleavage, impaired efferocytosis, and a defective RvD1:LTB₄ ratio. Macrophages from MerTK^CR mice were resistant to CM-induced efferocytosis defects and had an improved RvD1:LTB₄ ratio. RvD1-stimulated macrophages prevented CM-induced MerTK cleavage and promoted efferocytosis. Together, these data suggest a new mechanism and a potential therapy to promote inflammation-resolution and efferocytosis in aging.

SUBMITTER: Rymut N

PROVIDER: S-EPMC6956736 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Resolvin D1 promotes efferocytosis in aging by limiting senescent cell-induced MerTK cleavage.

Rymut Nicholas N Heinz Justin J Sadhu Sudeshna S Hosseini Zeinab Z Riley Colin O CO Marinello Michael M Maloney Jackson J MacNamara Katherine C KC Spite Matthew M Fredman Gabrielle G

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20191126 1

Inflammation-resolution is mediated by the balance between specialized pro-resolving mediators (SPMs) like resolvin D1 (RvD1) and pro-inflammatory factors, like leukotriene B<sub>4</sub> (LTB<sub>4</sub>). A key cellular process of inflammation-resolution is efferocytosis. Aging is associated with defective inflammation-resolution and the accumulation of pro-inflammatory senescent cells (SCs). Therefore, understanding mechanism(s) that underpin this impairment is a critical gap. Here, using a mo ...[more]

PMID: 31914705

Similar Datasets

Project description:Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that binds to low-density lipoprotein receptors. Efferocytosis is the process by which phagocytes remove apoptotic cells. Both PCSK9 and efferocytosis play important roles in regulating redox biology and inflammation, the key factors contributing to vascular aging. This study was designed to investigate the impact of PCSK9 on efferocytosis in endothelial cells (ECs) and its implications in vascular aging. Methods and Results: Studies were performed in primary human aortic ECs (HAECs) and primary mouse aortic ECs (MAECs) isolated from male wild-type (WT) and PCSK9-/- mice, and in young and aged mice treated with saline or the PCSK9 inhibitor Pep2-8. Our findings include that recombinant PCSK9 protein induces defective efferocytosis and aging marker senescence-associated-β-galactosidase (SA-β-gal) expression in ECs, while PCSK9-/- restores efferocytosis and inhibits SA-β-gal activity. Further studies in aged mice showed that endothelial deficiency of MerTK, a critical receptor for efferocytosis that allows phagocytes to detect the presence of apoptotic cells, may be an indicator of vascular dysfunction in the aortic arch. Pep2-8 treatment markedly restored efferocytosis in endothelium from the aged mice. A proteomics study in the aortic arch from aged mice revealed that Pep2-8 administration significantly downregulates expression of NOX4, MAPK subunits, NF-κB, and secretion of pro-inflammatory cytokines, all known to promote vascular aging. Immunofluorescent staining showed that Pep2-8 administration upregulates expression of eNOS and downregulates expression of pro-IL-1β, NF-κB and p22phox compared to saline treated group. Conclusions: These findings provide initial evidence for the ability of aortic ECs to accomplish efferocytosis and argue for a role of PCSK9 in attenuating EC efferocytosis, thereby leading to vascular dysfunction and acceleration in vascular aging.

Dataset Information

Resolvin D1 promotes efferocytosis in aging by limiting senescent cell-induced MerTK cleavage.

Publications

Resolvin D1 promotes efferocytosis in aging by limiting senescent cell-induced MerTK cleavage.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets