Executioner caspases 3 and 7 are dispensable for intestinal epithelium turnover and homeostasis at steady state

Abstract

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 (Casp3/7ΔIEC), 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 Casp3/7ΔIEC 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.

Caspase-7 and acid sphingomyelinase: partner repairmans of gasdermin and perforin pores

“…Another related work by Farzaneh Ghazavia et al recently reported that caspase-3 and caspase-7 are dispensable for IEC turnover and homeostasis at a steady state. 5 Considering the results from Kengo Nozaki et al together, we can conclude that caspase-7 exerts the function of pore repair in pathological condition of IECs, but is redundant in the physiological condition of IECs. When working as an executioner of apoptosis, the pore repair function of caspase-7 seems to be shut down by some unknown mechanism.…”

Apoptotic cell death in disease—Current understanding of the NCCD 2023

“…Moreover, the clearance of Casp9 −/− thymocytes seems to occur in a caspase-independent fashion [1310]. In the same line, although apoptosis is widely believed to be crucial for epithelial cell death and shedding in the intestine, during steady state, executioner CASP3 and CASP7 are dispensable for intestinal epithelial cell turnover at the top of intestinal villi, intestinal tissue dynamics, microbiome, and immune cell composition, suggesting high redundancy in non-challenged conditions [464]. Apparently at odds with these observations, Casp3 −/− mice were reported to have abnormally increased numbers of splenic B cells manifesting increased proliferative capacity [1311], as well as a dysregulated activity in bone marrow stromal stem cells that attenuated osteogenic differentiation [1312].…”

“…In this context, it is interesting to note that CASP3-or CASP7-deficient mice display an altered gut microbiome [463], which may play a hitherto unexplored role in multiple autoimmune and inflammatory disorders beyond intestinal conditions. However, it has recently been found that under steady state conditions the absence of CASP3 and CASP7 in the intestinal epithelial cells apparently neither affects the microbiome nor causes spontaneous inflammation, suggesting that apoptosis may be dispensable for intestinal epithelium turnover and homeostasis at baseline [464].…”