title: The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury.
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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hua-Bing
authors.initials: HB
authors.lastname: Li
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
authors.forename: Jiyu
authors.initials: J
authors.lastname: Tong
authors.affiliation: Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA.
authors.forename: Xinshou
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Koch Institute for Integrative Cancer Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
authors.forename: Naniye Malli
authors.initials: NM
authors.lastname: Cetinbas
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Till
authors.initials: T
authors.lastname: Strowig
authors.affiliation: Koch Institute for Integrative Cancer Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
authors.forename: Fred C
authors.initials: FC
authors.lastname: Lam
authors.affiliation: Hematology Oncology Fellowship Program, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Henao-Mejia
authors.affiliation: Koch Institute for Integrative Cancer Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
authors.forename: Omer
authors.initials: O
authors.lastname: Yilmaz
authors.affiliation: Division of Infectious Diseases and Immunology, Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. richard.flavell@yale.edu.|Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D001853:Bone Marrow / Q000378:metabolism / Q000528:radiation effects; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D007413:Intestinal Mucosa / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011832:Radiation Injuries / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D014916:Whole-Body Irradiation
chemical_list: C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D004247:DNA; D020170:Caspase 1