![]() Here, we sought to clarify and determine the role of Caspase-8 in the homeostasis of endothelial cells in adult mice. Intriguingly, when Casp8 deletion was induced in the endothelium post-partum, mice were relatively healthy but displayed necroptosis-independent impaired retinal angiogenesis. This is partially ameliorated by the loss of TNF receptors indicating that while TNF contributes to disease, other pro-death ligands such as Toll-like receptor (TLR) agonists may also promote this lethal phenotype. Gene-targeted mice lacking Caspase-8 in all tissues, and mice with endothelial cell-specific deletion of Casp8, die in utero due to the aberrant induction of necroptosis. More specifically, TNF-induced RIPK1 signaling can trigger Caspase-8-dependent apoptosis, or in the absence of Caspase-8 activity can associate with RIPK3 and MLKL to cause necroptosis –a lytic form of cell death implicated in the pathogenesis of numerous inflammatory disorders including Crohn’s disease and ulcerative colitis. For example, while TNF-induced RIPK1 signaling can promote pro-survival NF-kB signaling, it can alternatively trigger cell death when the activities of pro-survival factors such as cFLIP or cIAP are insufficient. Paradoxically, these same ligands can promote cell proliferation and survival, depending on the relative stoichiometry of intracellular adaptor and effector molecules. Inflammatory ligands, such as tumor necrosis factor (TNF), are key inducers of programmed cell death when they bind their cognate receptors. Programmed cell death is essential for the organized removal of diseased and dysfunctional cells. These data support a critical role for Caspase-8 in preserving gut vascular integrity in the face of microbial commensals. 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. This lethal phenotype was prevented in compound mutant mice that lacked the necroptotic cell death effector, MLKL. 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. Extensive whole body vascular gene targeting was confirmed, yet the dominant phenotype was fatal hemorrhagic lesions exclusively within the small intestine. ![]() To address this question, we used an inducible Cre recombinase system to delete endothelial Casp8 in 6-week-old conditionally gene-targeted mice. Whether endothelial Caspase-8 is also required for cardiovascular patency during adulthood was unknown. This is a developmentally essential function because in utero deletion of endothelial Caspase-8 causes systemic circulatory collapse during embryogenesis. Caspase-8 transduces signals from death receptor ligands, such as tumor necrosis factor, to drive potent responses including inflammation, cell proliferation or cell death.
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