Skip to main content

ODC (Ornithine Decarboxylase)-Dependent Putrescine Synthesis Maintains MerTK (MER Tyrosine-Protein Kinase) Expression to Drive Resolution.

Citation
Yurdagul, A., et al. “Odc (Ornithine Decarboxylase)-Dependent Putrescine Synthesis Maintains Mertk (Mer Tyrosine-Protein Kinase) Expression To Drive Resolution.”. Arteriosclerosis, Thrombosis, And Vascular Biology, pp. e144-e159.
Center Columbia University
Author Arif Yurdagul, Na Kong, Brennan D Gerlach, Xiaobo Wang, Patrick Ampomah, George Kuriakose, Wei Tao, Jinjun Shi, Ira Tabas
Keywords atherosclerosis, histones, inflammation, macrophages, putrescine
Abstract

OBJECTIVE: ODC (ornithine decarboxylase)-dependent putrescine synthesis promotes the successive clearance of apoptotic cells (ACs) by macrophages, contributing to inflammation resolution. However, it remains unknown whether ODC is required for other arms of the resolution program. Approach and Results: RNA sequencing of ODC-deficient macrophages exposed to ACs showed increases in mRNAs associated with heightened inflammation and decreases in mRNAs related to resolution and repair compared with WT (wild type) macrophages. In zymosan peritonitis, myeloid ODC deletion led to delayed clearance of neutrophils and a decrease in the proresolving cytokine, IL (interleukin)-10. Nanoparticle-mediated silencing of macrophage ODC in a model of atherosclerosis regression lowered IL-10 expression, decreased efferocytosis, enhanced necrotic core area, and reduced fibrous cap thickness. Mechanistically, ODC deletion lowered basal expression of MerTK (MER tyrosine-protein kinase)-an AC receptor-via a histone methylation-dependent transcriptional mechanism. Owing to lower basal MerTK, subsequent exposure to ACs resulted in lower MerTK-Erk (extracellular signal-regulated kinase) 1/2-dependent IL-10 production. Putrescine treatment of ODC-deficient macrophages restored the expression of both MerTK and AC-induced IL-10.

CONCLUSIONS: These findings demonstrate that ODC-dependent putrescine synthesis in macrophages maintains a basal level of MerTK expression needed to optimally resolve inflammation upon subsequent AC exposure. Graphic Abstract: A graphic abstract is available for this article.

Year of Publication
2021
Journal
Arteriosclerosis, thrombosis, and vascular biology
Volume
41
Issue
3
Number of Pages
e144-e159
Date Published
12/2021
ISSN Number
1524-4636
DOI
10.1161/ATVBAHA.120.315622
Alternate Journal
Arterioscler Thromb Vasc Biol
PMID
33406854
PMCID
PMC8034502
Download citation