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The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury

Bo HuDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USAChengcheng JinDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USAHuabing LiDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USAJiyu TongBiomedical Translational Research Institute, Jinan University, Guangzhou 510632, ChinaXinshou OuyangSection of Digestive Diseases, Yale University, New Haven, CT 06520, USANaniye Mallı CetinbasKoch Institute for Integrative Cancer Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USAShu ZhuDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USATill StrowigDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USAFred C. LamKoch Institute for Integrative Cancer Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USAChen ZhaoHematology Oncology Fellowship Program, National Institutes of Health, Bethesda, MD 20892, USAJorge Henao‐MejiaDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USAÖmer YılmazKoch Institute for Integrative Cancer Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USAKatherine A. FitzgeraldDivision of Infectious Diseases and Immunology, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USAStephanie C. EisenbarthDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USAEran ElinavDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USARichard A. FlavellDepartment of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA

2016en

ABI

Annotatsiya

Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Our results suggest that AIM2 may be a new therapeutic target for ionizing radiation exposure.

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DOI: 10.1126/science.aaf7532

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