Radiation-Induced Macrophage Senescence Impairs Resolution Programs and Drives Cardiovascular Inflammation.

Abstract

Radiation is associated with tissue damage and increased risk of atherosclerosis, but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that were associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known proresolving ligand, promoted swift resolution and restored efferocytosis in sublethally irradiated mice. Irradiated macrophages exhibited several features of senescence, including increased expression of p16INK4A and p21, heightened levels of SA-β-gal, COX-2, several proinflammatory cytokines/chemokines, and oxidative stress (OS) in vitro, and when transferred to mice, they exacerbated inflammation in vivo. Mechanistically, heightened OS in senescent macrophages led to impairment in their ability to carry out efficient efferocytosis, and treatment with RvD1 reduced OS and improved efferocytosis. Sublethally irradiated Ldlr -/- mice exhibited increased plaque necrosis, p16INK4A cells, and decreased lesional collagen compared with nonirradiated controls, and treatment with RvD1 significantly reduced necrosis and increased lesional collagen. Removal of p16INK4A hematopoietic cells during advanced atherosclerosis with p16-3MR mice reduced plaque necrosis and increased production of key intraplaque-resolving mediators. Our results demonstrate that sublethal radiation drives macrophage senescence and efferocytosis defects and suggest that RvD1 may be a new therapeutic strategy to limit radiation-induced tissue damage.

• Authors: Sudeshna Sadhu, Christa Decker, Brian E Sansbury, Michael Marinello, Allison Seyfried, Jennifer Howard, Masayuki Mori, Zeinab Hosseini, Thilaka Arunachalam, Aloke V Finn, John M Lamar, David Jourd'heuil, Liang Guo, Katherine C MacNamara, Matthew Spite, Gabrielle Fredman
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 207 Issue 7 Pg. 1812-1823 (10 01 2021) ISSN: 1550-6606 [Electronic] United States
• PMID: 34462312 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by The American Association of Immunologists, Inc.

Chemical References

• resolvin D1
• Docosahexaenoic Acids
• Ptgs2 protein, mouse
• Cyclooxygenase 2

Topics

• Animals
• Atherosclerosis (genetics, immunology)
• Cardiovascular Diseases (immunology)
• Cells, Cultured
• Cellular Senescence
• Cyclooxygenase 2 (metabolism)
• Docosahexaenoic Acids (metabolism)
• Genes, p16
• Hematopoietic Stem Cells (physiology)
• Humans
• Inflammation
• Macrophages (immunology)
• Mice
• Mice, Knockout
• Radiation
• Radiation Injuries (immunology)
• Wound Healing (radiation effects)