Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation.
Apoptosis is often accompanied by the degradation of chromosomal DNA. Caspase-activated DNase (CAD) is an endonuclease that is activated in dying cells, whereas DNase II is present in the lysosomes of macrophages. Here, we show that CAD(-/-) thymocytes did not undergo apoptotic DNA degradation. But, when apoptotic cells were phagocytosed by macrophages, their DNA was degraded by DNase II. The thymus of DNase II(-/-)CAD(-/-) embryos contained many foci carrying undigested DNA and the cellularity was severely reduced due to a block in T cell development. The interferon-beta gene was strongly up-regulated in the thymus of DNase II(-/-)CAD(-/-) embryos, suggesting that when the DNA of apoptotic cells is left undigested, it can activate innate immunity leading to defects in thymic development.
Kawane
Kohki
K
Department of Genetics, Osaka University Medical School, Japan.
Fukuyama
Hidehiro
H
Yoshida
Hideyuki
H
Nagase
Hiroko
H
Ohsawa
Yoshiyuki
Y
Uchiyama
Yasuo
Y
Okada
Kazuhisa
K
Iida
Tetsuya
T
Nagata
Shigekazu
S
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D003851:Deoxyribonucleases / Q000172:deficiency* / Q000235:genetics; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics; D005260:Female; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D013950:Thymus Gland / Q000196:embryology* / Q000276:immunology / Q000378:metabolism
D016898:Interferon-alpha; D016899:Interferon-beta; D004247:DNA; D003851:Deoxyribonucleases; D004706:Endodeoxyribonucleases; C109663:caspase-activated deoxyribonuclease; C019329:deoxyribonuclease II