Arif Yurdagul1, Na Kong2, Brennan D Gerlach1, Xiaobo Wang1, Patrick Ampomah1, George Kuriakose1, Wei Tao2, Jinjun Shi2, Ira Tabas1,3,4. 1. Department of Medicine (A.Y., B.D.G., X.W., P.A., G.K., I.T.), Columbia University Irving Medical Center, New York, NY. 2. Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.K., W.T., J.S.). 3. Department of Physiology (I.T.), Columbia University Irving Medical Center, New York, NY. 4. Department of Pathology and Cell Biology, Columbia University, New York, NY (I.T.).
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.
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.
Authors: Arif Yurdagul; Manikandan Subramanian; Xiaobo Wang; Scott B Crown; Olga R Ilkayeva; Lancia Darville; Gopi K Kolluru; Christina C Rymond; Brennan D Gerlach; Ze Zheng; George Kuriakose; Christopher G Kevil; John M Koomen; John L Cleveland; Deborah M Muoio; Ira Tabas Journal: Cell Metab Date: 2020-01-30 Impact factor: 27.287
Authors: Shuang Zhang; Samuel Weinberg; Matthew DeBerge; Anastasiia Gainullina; Matthew Schipma; Jason M Kinchen; Issam Ben-Sahra; David R Gius; Laurent Yvan-Charvet; Navdeep S Chandel; Paul T Schumacker; Edward B Thorp Journal: Cell Metab Date: 2018-12-27 Impact factor: 27.287
Authors: Charles N Serhan; Sue D Brain; Christopher D Buckley; Derek W Gilroy; Christopher Haslett; Luke A J O'Neill; Mauro Perretti; Adriano G Rossi; John L Wallace Journal: FASEB J Date: 2007-02 Impact factor: 5.191