Abstract
Intestinal homeostasis and the maintenance of the intestinal epithelial barrier are essential components of host defense during gastrointestinal Salmonella Typhimurium infection. Both require a strict regulation of cell death. However, the molecular pathways regulating epithelial cell death have not been completely understood. Here, we elucidated the contribution of central mechanisms of regulated cell death and upstream regulatory components during gastrointestinal infection. Mice lacking Caspase-8 in the intestinal epithelium are highly sensitive towards bacterial induced enteritis and intestinal inflammation, resulting in an enhanced lethality of these mice. This phenotype was associated with an increased STAT1 activation during Salmonella infection. Cell death, barrier breakdown and systemic infection were abrogated by an additional deletion of STAT1 in Casp8ΔIEC mice. In the absence of epithelial STAT1, loss of epithelial cells was abolished which was accompanied by a reduced Caspase-8 activation. Mechanistically, we demonstrate that epithelial STAT1 acts upstream of Caspase-8-dependent as well as -independent cell death and thus might play a major role at the crossroad of several central cell death pathways in the intestinal epithelium. In summary, we uncovered that transcriptional control of STAT1 is an essential host response mechanism that is required for the maintenance of intestinal barrier function and host survival.
Highlights
The invasive bacterium Salmonella enterica is a common gastrointestinal pathogen that causes severe foodborne illness in humans worldwide[1]
Stat1ΔIEC mice lost body weight viral pathogens is associated with epithelial cell death during the initial phase of infection and often accompanied by tissue injury responses involving epithelial renewal[37,38]
When looking machinery and the essential upstream components in gastroat barrier function and cell shedding, we observed that the lack of intestinal infection relevant for therapeutic aspects is limited so epithelial STAT1 strongly diminished extrusion of epithelial cells far
Summary
The invasive bacterium Salmonella enterica is a common gastrointestinal pathogen that causes severe foodborne illness in humans worldwide[1]. We as indicated by H&E staining and quantification of histological uncovered that the transcription factor STAT1 induces gene tissue damage (Fig. 1B, D) In line with this observation, expression of several key members of central cell death pathways visualization of cell death by TUNEL (terminal deoxynucleotidyl and controls the activation of Caspase-8-dependent and -inde- transferase dUTP nick end labeling) assay as well as characterizapendent cell death in the intestinal epithelium during gastro- tion of intestinal barrier integrity via E-Cadherin Induced enteritis Previously, we have shown that Caspase-8 plays a key role during Salmonella infection by mediating epithelial apoptosis expression of the intestinal epithelial cell (IEC) marker Villin was reduced in Casp8ΔIEC mice (Fig. 2D). Previous studies have demonstrated that the initial phase of gastrointestinal infection, as lack of this transcription factor in Casp8ΔIEC mice was sufficient to block excessive cell death and lethality
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