biostudies-literatureSadhu SHHS | NIH | National Institute of General Medical SciencesFondation LeducqNHLBI NIH HHSHHS | NIH | National Heart, Lung, and Blood InstituteNIGMS NIH HHS1812-1823https://www.ebi.ac.uk/biostudies/studies/S-EPMC8555670biostudies-literatureUnknown207(7)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 p16^INK4A 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 <i>Ldlr</i> ^-/- mice exhibited increased plaque necrosis, p16^INK4A cells, and decreased lesional collagen compared with nonirradiated controls, and treatment with RvD1 significantly reduced necrosis and increased lesional collagen. Removal of p16^INK4A 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.Journal of immunology (Baltimore, Md. : 1950)Radiation-Induced Macrophage Senescence Impairs Resolution Programs and Drives Cardiovascular Inflammation.PMC8555670HL153019R01 HL142807R35GM131842P01 GM095467R01 HL153019R01 HL106173R56 HL142807HL106173HL14112718CVD02HL142807R35 GM131842GM095467R01 HL141127Arunachalam TMarinello MSansbury BEHoward JSadhu SSpite MSeyfried AMori MDecker CGuo LFredman GFinn AVJourd'heuil DMacNamara KCLamar JMHosseini ZfalseRadiation-Induced Macrophage Senescence Impairs Resolution Programs and Drives Cardiovascular Inflammation.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 p16^INK4A 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 <i>Ldlr</i> ^-/- mice exhibited increased plaque necrosis, p16^INK4A cells, and decreased lesional collagen compared with nonirradiated controls, and treatment with RvD1 significantly reduced necrosis and increased lesional collagen. Removal of p16^INK4A 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.2021-01-01T00:00:00Z2021 Oct2025-04-04T19:52:13.936Z2025-02-19T02:24:40.393ZS-EPMC85556703446231210.4049/jimmunol.2100284