期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：6
DOI：10.1073/pnas.2024508119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Historically, programmed cell death by apoptosis is considered crucial for proper intestinal organogenesis and gut homeostasis. To challenge this concept, we generated caspase-3 and -7 double knockout mice specifically in intestinal epithelial cells (IECs). However, absence of apoptosis in IECs elicits neither morphological and inflammatory changes nor intestinal dysbiosis during gut homeostasis at steady state. This demonstrates the robustness of intestinal homeostasis at steady state for the absence of caspase-3/7 and shows that in contrast to caspase-8, which keeps necroptosis and associated inflammation in check, caspase-3/7–dependent apoptosis of IECs in homeostatic conditions is dispensable for normal intestinal development, immune cell composition, and microbiome control.
Apoptosis is widely believed to be crucial for epithelial cell death and shedding in the intestine, thereby shaping the overall architecture of the gastrointestinal tract, but also regulating tolerance induction, pinpointing a role of apoptosis intestinal epithelial cell (IEC) turnover and maintenance of barrier function, and in maintaining immune homeostasis. To experimentally address this concept, we generated IEC-specific knockout mice that lack both executioner caspase-3 and caspase-7 (
Casp3/7
ΔIEC), which are the converging point of the extrinsic and intrinsic apoptotic pathway. Surprisingly, the overall architecture, cellular landscape, and proliferation rate remained unchanged in these mice. However, nonapoptotic cell extrusion was increased in
Casp3/7
ΔIEC mice, compensating apoptosis deficiency, maintaining the same physiological level of IEC shedding. Microbiome richness and composition stayed unaffected, bearing no sign of dysbiosis. Transcriptome and single-cell RNA sequencing analyses of IECs and immune cells revealed no differences in signaling pathways of differentiation and inflammation. These findings demonstrate that during homeostasis, apoptosis per se is dispensable for IEC turnover at the top of intestinal villi intestinal tissue dynamics, microbiome, and immune cell composition.
