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Science. 2016 Nov 11;354(6313):765-768.

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

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
3
Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA.
4
Koch Institute for Integrative Cancer Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
5
Hematology Oncology Fellowship Program, National Institutes of Health, Bethesda, MD 20892, USA.
6
Division of Infectious Diseases and Immunology, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
7
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
8
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. richard.flavell@yale.edu.
9
Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA.

Abstract

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.

PMID:
27846608
PMCID:
PMC5640175
DOI:
10.1126/science.aaf7532
[Indexed for MEDLINE]
Free PMC Article

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