Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury.
Animals
Apoptosis
/ drug effects
Arginase
/ metabolism
Arginine
/ pharmacology
ELAV-Like Protein 1
/ metabolism
Gene Deletion
Guanine Nucleotide Exchange Factors
/ genetics
Humans
Jurkat Cells
Macrophages
/ drug effects
Male
Mice, Inbred C57BL
Myeloid Cells
/ drug effects
Ornithine Decarboxylase
/ metabolism
Phagocytosis
/ drug effects
Putrescine
/ biosynthesis
RNA Stability
/ drug effects
RNA, Messenger
/ genetics
rac1 GTP-Binding Protein
/ metabolism
arginase
arginine
atherosclerosis
atherosclerosis regression
efferocytosis
inflammation resolution
intracellular metabolism
macrophage
polyamines
putrescine
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
03 03 2020
03 03 2020
Historique:
received:
17
04
2019
revised:
23
09
2019
accepted:
06
01
2020
pubmed:
1
2
2020
medline:
2
7
2021
entrez:
1
2
2020
Statut:
ppublish
Résumé
Continual efferocytic clearance of apoptotic cells (ACs) by macrophages prevents necrosis and promotes injury resolution. How continual efferocytosis is promoted is not clear. Here, we show that the process is optimized by linking the metabolism of engulfed cargo from initial efferocytic events to subsequent rounds. We found that continual efferocytosis is enhanced by the metabolism of AC-derived arginine and ornithine to putrescine by macrophage arginase 1 (Arg1) and ornithine decarboxylase (ODC). Putrescine augments HuR-mediated stabilization of the mRNA encoding the GTP-exchange factor Dbl, which activates actin-regulating Rac1 to facilitate subsequent rounds of AC internalization. Inhibition of any step along this pathway after first-AC uptake suppresses second-AC internalization, whereas putrescine addition rescues this defect. Mice lacking myeloid Arg1 or ODC have defects in efferocytosis in vivo and in atherosclerosis regression, while treatment with putrescine promotes atherosclerosis resolution. Thus, macrophage metabolism of AC-derived metabolites allows for optimal continual efferocytosis and resolution of injury.
Identifiants
pubmed: 32004476
pii: S1550-4131(20)30001-2
doi: 10.1016/j.cmet.2020.01.001
pmc: PMC7173557
mid: NIHMS1569352
pii:
doi:
Substances chimiques
ELAV-Like Protein 1
0
Elavl1 protein, mouse
0
Guanine Nucleotide Exchange Factors
0
Mcf2 protein, mouse
0
RNA, Messenger
0
Arginine
94ZLA3W45F
Arginase
EC 3.5.3.1
rac1 GTP-Binding Protein
EC 3.6.5.2
Ornithine Decarboxylase
EC 4.1.1.17
Putrescine
V10TVZ52E4
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
518-533.e10Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL128349
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 HL132412
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA076292
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL075662
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Organisme : NHLBI NIH HHS
ID : F32 HL137398
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL087123
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001873
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063608
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL149264
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127464
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK089312
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
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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