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

Bo Hu; Chengcheng Jin; Hua Bing Li; Jiyu Tong; Xinshou Ouyang; Naniye Malli Cetinbas; Shu Zhu; Till Strowig; Fred C. Lam; Chen Zhao; Jorge Henao-Mejia; Omer Yilmaz; Katherine A. Fitzgerald; Stephanie C. Eisenbarth; Eran Elinav; Richard A. Flavell

doi:10.1126/science.aaf7532

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

Bo Hu, Chengcheng Jin, Hua Bing Li, Jiyu Tong, Xinshou Ouyang, Naniye Malli Cetinbas, Shu Zhu, Till Strowig, Fred C. Lam, Chen Zhao, Jorge Henao-Mejia, Omer Yilmaz, Katherine A. Fitzgerald, Stephanie C. Eisenbarth, Eran Elinav, Richard A. Flavell^*

^*Corresponding author for this work

Medicine, Allergy Division

Research output: Contribution to journal › Article › peer-review

305 Scopus citations

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.

Original language	English (US)
Pages (from-to)	765-768
Number of pages	4
Journal	Science
Volume	354
Issue number	6313
DOIs	https://doi.org/10.1126/science.aaf7532
State	Published - Nov 11 2016

Funding

We thank V. M. Dixit, N. Kayagaki, and E. S. Alnemri for sharing materials and reagents, and V. A. Rathinam for technical advice. We thank P. Bongiorni for assistance with radiation experiments. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. H.-B.L. is supported by NIH T32 2T32DK007356. This work was supported by the Howard Hughes Medical Institute (R.A.F.).

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Hu, B., Jin, C., Li, H. B., Tong, J., Ouyang, X., Cetinbas, N. M., Zhu, S., Strowig, T., Lam, F. C., Zhao, C., Henao-Mejia, J., Yilmaz, O., Fitzgerald, K. A., Eisenbarth, S. C., Elinav, E., & Flavell, R. A. (2016). The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science, 354(6313), 765-768. https://doi.org/10.1126/science.aaf7532

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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.",

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

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