Caspase‐8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice

Tisch, Nathalie; Mogler, Carolin; Stojanović, Ana; Luck, Robert; Korhonen, Emilia A.; Ellerkmann, Alexander; Adler, Heike; Singhal, Mahak; Schermann, Géza; Erkert, Lena; Patankar, Jay V.; Karakatsani, Andromachi; Scherr, Anna-Lena; Fuchs, Yaron; Cerwenka, Adelheid; Wirtz, Stefan; Köhler, Bruno; Augustin, Hellmut G.; Becker, Christoph; Schmidt, Thomas; Almodóvar, Carmen Ruiz de

doi:10.15252/emmm.202114121

Cited by 15 publications

(14 citation statements)

References 79 publications

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“…However, as resident cell types within the gastrointestinal wall cooperatively maintain gut shape and function [ 49 ], it stands to reason that endothelial defects also precipitate inflammatory gut disease. Indeed, upon completion of our study, another group has separately reported that loss of endothelial Caspase-8 in adult mice precipitates small intestinal hemorrhage [ 50 ]. Our findings largely overlap or extend the observations of Tisch and colleagues [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, upon completion of our study, another group has separately reported that loss of endothelial Caspase-8 in adult mice precipitates small intestinal hemorrhage [ 50 ]. Our findings largely overlap or extend the observations of Tisch and colleagues [ 50 ]. For instance, while polymicrobial products broadly trigger hemorrhage in C8-endo mice, we find that endogenous TLR4-signaling is especially critical for this necroptotic phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Endothelial Caspase-8 prevents fatal necroptotic hemorrhage caused by commensal bacteria

et al. 2022

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Caspase-8 transduces signals from death receptor ligands, such as tumor necrosis factor, to drive potent responses including inflammation, cell proliferation or cell death. This is a developmentally essential function because in utero deletion of endothelial Caspase-8 causes systemic circulatory collapse during embryogenesis. Whether endothelial Caspase-8 is also required for cardiovascular patency during adulthood was unknown. To address this question, we used an inducible Cre recombinase system to delete endothelial Casp8 in 6-week-old conditionally gene-targeted mice. Extensive whole body vascular gene targeting was confirmed, yet the dominant phenotype was fatal hemorrhagic lesions exclusively within the small intestine. The emergence of these intestinal lesions was not a maladaptive immune response to endothelial Caspase-8-deficiency, but instead relied upon aberrant Toll-like receptor sensing of microbial commensals and tumor necrosis factor receptor signaling. This lethal phenotype was prevented in compound mutant mice that lacked the necroptotic cell death effector, MLKL. Thus, distinct from its systemic role during embryogenesis, our data show that dysregulated microbial- and death receptor-signaling uniquely culminate in the adult mouse small intestine to unleash MLKL-dependent necroptotic hemorrhage after loss of endothelial Caspase-8. These data support a critical role for Caspase-8 in preserving gut vascular integrity in the face of microbial commensals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Endothelial Caspase-8 prevents fatal necroptotic hemorrhage caused by commensal bacteria

et al. 2022

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“…However, it also represents the molecular switch that controls apoptosis, necroptosis and pyroptosis 33 . Caspase-8 has been identi ed to be a pro-survival factor for gut epithelial cells 34 and mature gut endothelial cells 22 . Caspase-8 is required to actively maintain vascular homeostasis in small bowel.…”

Section: Discussionmentioning

confidence: 99%

“…Caspase-8 is required to actively maintain vascular homeostasis in small bowel. Thus, loss of caspse-8 in gut endothelial cells leads to gut hemorrhages, in ammation, and GVB hyper-permeability to FITC-dextran 70 kDa 22 . Caspase-8 de ciency also causes embryonic lethality in mice 35 .…”

Section: Discussionmentioning

confidence: 99%

Berberine reduces enteroglial-derived S100B production to alleviate gut vascular barrier damage

Feng

Kang

et al. 2022

Preprint

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Gut vascular barrier (GVB) controls the systemic dissemination of bacteria. Enteric glial cells (EGCs) in mucosa as a component of gut vascular unit can amplify inflammation via S100B. Berberine (BBR) is an alkaloid that can alleviate gut inflammation and regulate EGCs activity. In this study, we aimed to unravel the mechanism by which BBR inhibited EGCs-derived S100B generation to protect GVB. In vivo BBR was given via oral gavage to mice who were subjected to 40% total body surface area burns. In vitro BBR, S100B and caspase-8 inhibitor Z-IETD-FMK were used to treat mouse intestinal microvascular endothelial cells (MIMECs). The results showed that (1) BBR lowered serum S100B concentration and decreased S100B accumulation in colonic mucosa; (2) BBR and S100B monoclonal antibody (S100BmAb) lowered burn-induced GVB hyperpermeability; (3) BBR antagonized the effect of S100B enema on GVB permeability; (4) S100B and Z-IETD-FMK increased the permeability of MIMECs and reduced the expression of caspase-8, β-catenin, occludin and VE-cadherin in MIMECs, while these effects of S100B were effectively antagonized by BBR treatment; (5) Z-IETD-FMK inhibited β-catenin expression in MIMECs. Collectively, our findings showed that S100B accumulation in gut mucosa damaged GVB, and BBR treatment alleviated GVB damage via modulation of caspase-8/β-catenin signaling pathways.

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“…In this context, CASP8-deficient enterocytes displayed decreased in vivo survival and migration potential [ 1483 ]. Specific deletion of Casp8 in endothelial cells results in small intestinal hemorrhage and bowel inflammation, suggesting a key role of CASP8 in vascular homeostasis in the small intestine [ 1484 ]. Loss of CASP8 catalytic activity specifically in intestinal epithelial cells induced intestinal inflammation similar to absence of CASP8 in the intestinal epithelium [ 1424 ].…”

Section: Extrinsic Apoptosis In Diseasementioning

confidence: 99%

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

et al. 2023

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Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

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Caspase‐8 in endothelial cells maintains gut homeostasis and prevents small bowel inflammation in mice

Cited by 15 publications

References 79 publications

Endothelial Caspase-8 prevents fatal necroptotic hemorrhage caused by commensal bacteria

Endothelial Caspase-8 prevents fatal necroptotic hemorrhage caused by commensal bacteria

Berberine reduces enteroglial-derived S100B production to alleviate gut vascular barrier damage

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

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