Abstract
We investigated the role of the inflammasome effector caspases-1 and -11 during Salmonella enterica serovar Typhimurium infection of murine intestinal epithelial cells (IECs). Salmonella burdens were significantly greater in the intestines of caspase-1/11 deficient (Casp1/11−/−), Casp1−/− and Casp11−/− mice, as compared to wildtype mice. To determine if this reflected IEC-intrinsic inflammasomes, enteroid monolayers were derived and infected with Salmonella. Casp11−/− and wildtype monolayers responded similarly, whereas Casp1−/− and Casp1/11−/− monolayers carried significantly increased intracellular burdens, concomitant with marked decreases in IEC shedding and death. Pretreatment with IFN-γ to mimic inflammation increased caspase-11 levels and IEC death, and reduced Salmonella burdens in Casp1−/− monolayers, while high intracellular burdens and limited cell shedding persisted in Casp1/11−/− monolayers. Thus caspase-1 regulates inflammasome responses in IECs at baseline, while proinflammatory activation of IECs reveals a compensatory role for caspase-11. These results demonstrate the importance of IEC-intrinsic canonical and non-canonical inflammasomes in host defense against Salmonella.
Highlights
Within the mammalian gastrointestinal (GI) tract, intestinal epithelial cells (IECs) provide the primary interface between the microbial-rich gut lumen and the underlying mucosal immune system
Typhimurium infection (12 h post-infection (p.i.)), the IECs lining the ceca of Naip1-6−/− and Nlrc4−/− mice were found to be heavily infected, containing densely packed microcolonies of intracellular Salmonella, which were only rarely observed in the IECs of wildtype mice [2]
Through bone marrow transplantation studies, as well as the use of Naip1-6ΔIEC−/− mice, the authors demonstrated this microcolony phenotype was caused by the loss of Naip-Nlrc4 inflammasome activation in IECs
Summary
Within the mammalian gastrointestinal (GI) tract, intestinal epithelial cells (IECs) provide the primary interface between the microbial-rich gut lumen and the underlying mucosal immune system. They play a central role in the coordination of mucosal homeostasis, tempering pro-inflammatory responses while remaining rapidly reactive to noxious stimuli such as enteric pathogens. The invasion and intracellular proliferation of this pathogen triggers the activation of IEC-intrinsic inflammasomes, resulting in the expulsion of infected IECs into the intestinal lumen The more rapidly these cells are shed, the less time is available for intracellular Salmonella to proliferate and invade surrounding IECs or translocate into the underlying lamina propria. The protective role for Naip was extremely acute as these mice were comparable to wildtype mice in Salmonella colonization of the cecum or histopathology at later time points (36 h p.i.)
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