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Caspase-1 plays a key role in inflammatory pathways by processing pro-IL-Iβ into the active cytokine mature IL-1β. Given its sequence similarity with the Caenorhabditis elegans cell death gene ced-3, it has long been speculated that caspase-1 may also play a role in cell death. However, an unequivocal role for caspase-1 in cell death has been questioned, and not definitively demonstrated. Furthermore, if caspase-1 does play a role in cell death, its position in the apoptotic hierarchy has not been clearly defined. Previous studies have shown that caspase-1 knockout (KO) mice and transgenic mice expressing a dominant-negative caspase-1 construct are resistant to ischemic brain injury. We provide direct evidence that caspase-1 plays a key role in neuronal cell death and that caspase-1 is an apical activator of the cell death pathway in the premitochondrial collapse stage. Furthermore, we demonstrate that Rip2/ Cardiak/Rick is a stress-inducible upstream modulator of procaspase-1 apoptotic activation. We provide evidence that Bid cleavage appears to be an important downstream effector of caspase-l-mediated cell death. Our data demonstrate that caspase-1 is an apical mediator of neuronal cell death during in vitro hypoxia, and confirmed in vivo in ischemia, and provide insights into the sequence of events involved in this pathological cell death process. [ABSTRACT FROM AUTHOR]

Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD),however, the cellular and molecular regulation of intestinal epithelial homeostasis remains largely undefined. Here, we show that the C-type lectin receptor LSECtin (Clec4g) on macrophages is required for protection against dextran sulfate sodiuminduced colitis. Mechanistically, LSECtin promotes apoptotic cell clearance by macrophages and induces the production of antiinflammatory/ tissue repair factors in an engulfment-dependent manner, which in turn stimulates epithelial cell proliferation. Deletion of LSECtin results in defective engulfment by colon macrophages, leading to aberrant proresolving factor production and impaired intestinal epithelium repair. Collectively, our findings suggest that LSECtindependent corpse clearance by macrophages can direct intestinal regeneration and maintenance of the mucosal barrier after injury. [ABSTRACT FROM AUTHOR]