Radiation-induced macrophage senescence impairs resolution programs and drives cardiovascular inflammation
| Autor: | Matthew Spite, Jennifer Howard, Zeinab F. Hosseini, Sudeshna Sadhu, Michael Marinello, Allison N. Seyfried, Masayuki Mori, Aloke V. Finn, John M. Lamar, Gabrielle Fredman, Brian E. Sansbury, David Jourd'heuil, Thilaka Arunachalam, Liang Guo, Christa Decker, Katherine C. MacNamara |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Senescence
Chemokine Necrosis Docosahexaenoic Acids Immunology Inflammation medicine.disease_cause Article Proinflammatory cytokine Mice medicine Immunology and Allergy Macrophage Animals Humans Efferocytosis Radiation Injuries Cells Cultured Cellular Senescence Mice Knockout Wound Healing Radiation biology business.industry Genes p16 Macrophages Atherosclerosis Hematopoietic Stem Cells Cardiovascular Diseases Cyclooxygenase 2 Cancer research biology.protein medicine.symptom business Oxidative stress |
| Zdroj: | J Immunol |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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