NAIP-NLRC4 Inflammasomes Coordinate Intestinal Epithelial Cell Expulsion with Eicosanoid and IL-18 Release via Activation of Caspase-1 and -8

Intestinal epithelial cells (IECs) form a critical barrier against pathogen invasion. By generation of mice in which inflammasome expression is restricted to IECs, we describe a coordinated epithelium-intrinsic inflammasome response in vivo. This response was sufficient to protect against Salmonella tissue invasion and involved a previously reported IEC expulsion that was coordinated with lipid mediator and cytokine production and lytic IEC death. Excessive inflammasome activation in IECs was sufficient to result in diarrhea and pathology. Experiments with IEC organoids demonstrated that IEC expulsion did not require other cell types. IEC expulsion was accompanied by a major actin rearrangement in neighboring cells that maintained epithelium integrity but did not absolutely require Caspase-1 or Gasdermin D. Analysis of Casp1–/–Casp8–/– mice revealed a functional Caspase-8 inflammasome in vivo. Thus, a coordinated IEC-intrinsic, Caspase-1 and -8 inflammasome response plays a key role in intestinal immune defense and pathology. [Display omitted] •NLRC4 activation in IECs leads to cell expulsion and IL-18 and eicosanoid release•NLRC4 in IECs is sufficient to protect from infection but can cause pathology•Caspase-1 and Gasdermin D are not necessary for NLRC4 signaling in IECs•Caspase-8 is activated downstream of NLRC4 Rauch et al. show that selective activation of the NLRC4 inflammasome in intestinal epithelial cells leads to a coordinated response that includes cell expulsion and eicosanoid and cytokine release. This is not fully dependent on Caspase-1, as cell expulsion can also be caused by Caspase-8 activated by NLRC4.