Efferocytosis induces macrophage proliferation to help resolve tissue injury.
DNase2a
Erk1/2 signaling
MerTK
Myc
atherosclerosis
efferocytosis
inflammation resolution
mTORC2/Rictor
macrophage
macrophage proliferation
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
07 12 2021
07 12 2021
Historique:
received:
23
03
2021
revised:
17
08
2021
accepted:
26
10
2021
pubmed:
17
11
2021
medline:
8
4
2022
entrez:
16
11
2021
Statut:
ppublish
Résumé
Apoptotic cell clearance by macrophages (efferocytosis) promotes resolution signaling pathways, which can be triggered by molecules derived from the phagolysosomal degradation of apoptotic cells. We show here that nucleotides derived from the hydrolysis of apoptotic cell DNA by phagolysosomal DNase2a activate a DNA-PKcs-mTORC2/Rictor pathway that increases Myc to promote non-inflammatory macrophage proliferation. Efferocytosis-induced proliferation expands the pool of resolving macrophages in vitro and in mice, including zymosan-induced peritonitis, dexamethasone-induced thymocyte apoptosis, and atherosclerosis regression. In the dexamethasone-thymus model, hematopoietic Rictor deletion blocked efferocytosing macrophage proliferation, apoptotic cell clearance, and tissue resolution. In atherosclerosis regression, silencing macrophage Rictor or DNase2a blocked efferocyte proliferation, apoptotic cell clearance, and plaque stabilization. In view of previous work showing that other types of apoptotic cell cargo can promote resolution in individual efferocytosing macrophages, the findings here suggest that signaling-triggered apoptotic cell-derived nucleotides can amplify this benefit by increasing the number of these macrophages.
Identifiants
pubmed: 34784501
pii: S1550-4131(21)00527-1
doi: 10.1016/j.cmet.2021.10.015
pmc: PMC8665147
mid: NIHMS1754748
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2445-2463.e8Subventions
Organisme : NCRR NIH HHS
ID : S10 RR027050
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL145228
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR025686
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127464
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL087123
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL159012
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL145131
Pays : United States
Organisme : NIH HHS
ID : S10 OD020056
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007343
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121307
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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