XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells

Abstract

In XIAP deficiency, ileitis is driven by TNFR1- and TNFR2-dependent targeting of TLR5-expressing Paneth and dendritic cells.

Deficiency in X-linked inhibitor of apoptosis protein promotes susceptibility to microbial triggers of intestinal inflammation

“…6K, right). Of note, central findings of our study including TNFR1- and microbiota-dependent Paneth cell dysfunction and intestinal inflammation in Xiap KO mice were independently observed by Wahida and colleagues ( 58 ), who reported spontaneous microbiota-dependent small intestinal inflammation in Xiap KO mice maintained under non-SPF conditions, whereas SPF or GF rederivation of these mice as well as cohousing with WT mice abrogated inflammation. Together, these findings illustrated how alterations in host genetics can elicit susceptibility to specific microbial triggers of intestinal inflammation and help to explain the observation of incomplete penetrance of CD in carriers of XIAP mutations.…”

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

“…We performed an in-depth analysis of the entire gastrointestinal tract, including macro and microarchitecture, microbiota, and transcriptomic analyses and did not detect any apparent phenotypic difference between the Casp3/7 ΔIEC transgenic mice and WT littermates ( Casp3/7 fl/fl ) at the level of development, differentiation, inflammation, and microbiome composition and diversity. The absence of any intestinal or systemic phenotype in Casp3/7 ΔIEC mice indicates that under steady-state conditions, apoptotic cell death is not required for intestinal homeostasis and for keeping a noninflammatory state by continuous sampling of apoptotic IECs by interdigiting phagocytic immune cells, as was elegantly demonstrated by Blander and coworkers ( 17 ), but also other mechanisms contribute to immune homeostasis, such as microbiota and their metabolites (butyrate and TLR ligands, for example), and diet (cruciferous vegetables, indoles, and aryl hydrocarbon receptor engagement for example) regulate innate lymphoid cells, dendritic cells (DCs), Treg, and Th17 cells ( 1 , 56 – 58 ). Our results with apoptosis-deficient IECs now provide genetic evidence that caspase-3/7–mediated apoptosis apparently is not needed for the continuous turnover of IECs at the top of the villi.…”

“…However, our data do not exclude a particularly important role of apoptosis in tolerance induction, microbiome shaping, tissue repair by apoptosis-induced proliferation during challenges, and control of intestinal infection. Indeed, a crucial role for apoptosis in IECs was demonstrated during different challenges, e.g., tolerance induction during barrier loss ( 17 ), modulation of anticancer immunosurveillance during chemotherapy ( 59 ), sensitivity to Clostridium difficile infection ( 58 ), and IEC apoptosis-dependent boosting of growth of multiple Enterobacteriaceae during dysbiosis ( 69 ). Recently the unique role of apoptosis during steady-state regeneration was shown in hair follicle stem cell (HFSC) self-renewal and differentiation.…”

“…This shows that during gut homeostasis at steady state the balance between cell death and cell proliferation can be achieved by redundant processes not driven by caspase-3 and caspase-7 in the IECs. However, the apoptotic modus in IECs might be required during conditions of challenges ( 17 , 58 – 60 ), as discussed above.…”

Cell Death-Related Ubiquitin Modifications in Inflammatory Syndromes: From Mice to Men

“…Mouse models were again of great help to gain insights into the role of XIAP in the regulation of immune system responses ( Table 1 ). Indeed, two recent works have shed new light on the role of XIAP deficiency in IBD pathogenesis, using Xiap −/− mice as a model [ 77 , 78 ]. In one case, the authors showed that XIAP-deficient mice have a reduced number of Paneth cells, as consequence of their death, which is TNF- and microbiota-dependent and RIPK1/RIPK3-mediated.…”