Abstract
Pattern recognition receptors (PRR), such as NOD-like receptors (NLRs), sense conserved microbial signatures, and host danger signals leading to the coordination of appropriate immune responses. Upon activation, a subset of NLR initiate the assembly of a multimeric protein complex known as the inflammasome, which processes pro-inflammatory cytokines and mediates a specialized form of cell death known as pyroptosis. The identification of inflammasome-associated genes as inflammatory bowel disease susceptibility genes implicates a role for the inflammasome in intestinal inflammation. Despite the fact that the functional importance of inflammasomes within immune cells has been well established, the contribution of inflammasome expression in non-hematopoietic cells remains comparatively understudied. Given that intestinal epithelial cells (IEC) act as a barrier between the host and the intestinal microbiota, inflammasome expression by these cells is likely important for intestinal immune homeostasis. Accumulating evidence suggests that the inflammasome plays a key role in shaping epithelial responses at the host–lumen interface with many inflammasome components highly expressed by IEC. Recent studies have exposed functional roles of IEC inflammasomes in mucosal immune defense, inflammation, and tumorigenesis. In this review, we present the main features of the predominant inflammasomes and their effector mechanisms contributing to intestinal homeostasis and inflammation. We also discuss existing controversies in the field and open questions related to their implications in disease. A comprehensive understanding of the molecular basis of intestinal inflammasome signaling could hold therapeutic potential for clinical translation.
Highlights
Intestinal homeostasis is governed by complex interactions between the host immune system, the vast constitutive antigenic load in the lumen, and the epithelial barrier
AMP, antimicrobial peptides; C. rod, Citrobacter rodentium; FlaTox, Legionella pneumophila flagellin fused to the N-terminal domain of Bacillus anthracis lethal factor; NAIP5, ligand delivered to cytosol; IEC, intestinal epithelial cells; NSAID, non-steroidal anti-inflammatory drugs; SI, small intestine; S
Studies have been conducted using IEC-specific IL-18 knockouts (IL-18ΔIEC) [110] and IEC-specific caspase-1 knockouts (Casp1ΔIEC) (Tables 2 and 3) [142]. These studies reported that caspase-1 activation and consequent IL-18 secretion by IEC during dextran sodium sulfate (DSS) colitis was associated with exacerbated inflammation and decreased goblet cell maturation [110, 142]. These findings are somewhat surprising, as NLRP6 deficiencies were previously associated with both decreased IL-18 levels [33] and goblet cell mucus secretion [34], which led to increased susceptibility to DSS-mediated intestinal injury
Summary
Intestinal homeostasis is governed by complex interactions between the host immune system, the vast constitutive antigenic load in the lumen, and the epithelial barrier Breakdown in this molecular dialog can lead to the development of chronic pathologies, such as inflammatory bowel diseases (IBD). Caspase-1 has two main functions, cleavage of pro-IL-1β and pro-IL-18 into their active forms for secretion [53, 54], and the induction of a specialized form of inflammatory cell death known as pyroptosis [55,56,57] Another form of inflammasome has been described which does not require a member of the NLR family, but instead contains members of the PYHIN family (PYD and HIN domain containing).
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