Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Yurdagul, A; Subramanian, M; Wang, X; Crown, SB; Ilkayeva, OR; Darville, L; Kolluru, GK; Rymond, CC; Gerlach, BD; Zheng, Z; Kuriakose, G; Kevil, CG; Koomen, JM; Cleveland, JL; Muoio, DM; Tabas, I

Published Date

  • March 3, 2020

Published In

Volume / Issue

  • 31 / 3

Start / End Page

  • 518 - 533.e10

PubMed ID

  • 32004476

Pubmed Central ID

  • 32004476

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2020.01.001

Language

  • eng

Conference Location

  • United States