Canonical and noncanonical inflammasomes in intestinal epithelial cells

Abstract

Inflammasomes are cytosolic, multimeric protein complexes capable of activating pro‐inflammatory cytokines such as IL‐1β and IL‐18, which play a key role in host defence. Inflammasome components are highly expressed in the intestinal epithelium. In recent years, studies have begun to demonstrate that epithelial‐intrinsic inflammasomes play a critical role in regulating epithelial homeostasis, both by defending the epithelium from pathogenic insult and through the regulation of the mucosal environment. However, the majority of research regarding inflammasome activation has focused on professional immune cells, such as macrophages. Here, we present an overview of the current understanding of inflammasome function in epithelial cells and at mucosal surfaces and, in particular, in the intestine.

Germ‐free and microbiota‐associated mice yield small intestinal epithelial organoids with equivalent and robust transcriptome/proteome expression phenotypes

“…Our follow‐up analysis extended this finding to also encompass the transcripts for a range of other inflammasome receptors (e.g., Naip1 , 2 , 5 , 6 , Nlrc4 ), inflammatory caspases (e.g., Caspase‐1 ) and downstream executors (e.g., GsdmD ), which all exhibited high expression in organoids and low to undetectable expression in epithelial cell line m‐IC c12 and fibroblast reference cells. Importantly, high expression of these inflammasome components in epithelial cells were reported previously (Hausmann, Sellin, & Hardt, ; Winsor, Krustev, Bruce, Philpott, & Girardin, ), further indicating that organoids more realistically represent the in vivo situation. The differential regulation of inflammasome components upon exposure to the proinflammatory cytokine TNF likely represents a preparation of epithelial cells to microbial exposure.…”

“…By contrast, organoids grown under optimal conditions retain expression also of such potential tumour suppressor genes. Notably, with regard to the widely discussed reciprocal interactions between microbiota and inflammasomes in the gut (Mamantopoulos et al, ; Robertson et al, ; Seo et al, ; Winsor et al, ), the expression of inflammasome components appears unaffected by the donor microbiota in small intestinal epithelial organoids. Thus, compared to classical tissue culture cell lines, organoids should be more realistic models to study the function of epithelial inflammasomes.…”

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

“…NLRP3 was shown to contribute to fibrosis development in a in vivo model of NASH, and patients with increasing levels of fibrosis exhibited increased NLRP3 mRNA levels [17,18]. High levels of inflammasome components are present in many epithelial tissues, where they have been shown to represent an important first line of defense [19]. Interestingly, a number of recent studies have highlighted the importance of NRLP3-dependent mucosal immunity also in inflammatory bowel diseases (IBD), which are frequently associated with cholestatic liver diseases.…”

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

“…The antibacterial function of inflammasomes is illustrated by the ability of various inflammasome sensor proteins to recognise and respond to bacterial ligands (Eldridge & Shenoy, 2015; Hayward et al, ), and the increased susceptibility to infection shown by mice with deletions in inflammasome components (Man, Karki, & Kanneganti, ; Lacey & Miao, 2019). Although inflammasomes have been best studied in myeloid cells, several inflammasome components, such as caspase‐4/11 and pro‐IL‐18, are also expressed in IECs (Man, ; Winsor, Krustev, Bruce, Philpott, & Girardin, ). The constitutive expression of caspase‐4/11 and NAIPs in IECs (Knodler et al, ; Sellin et al, ) might allow rapid sensing of Gram‐negative pathogens at mucosal sites.…”

“…The constitutive expression of caspase‐4/11 and NAIPs in IECs (Knodler et al, ; Sellin et al, ) might allow rapid sensing of Gram‐negative pathogens at mucosal sites. The importance of inflammasomes in innate immune signalling in the gut in response to microbial and sterile insults, as well as the contribution of inflammasomes to diseases such as IBD, cancer and obesity and their role in the maintenance of the intestinal microbiota have been reviewed elsewhere (Levy, Kolodziejczyk, Thaiss, & Elinav, ; Man, ; Winsor et al, ). This review focuses on the host's detection of enteric pathogens via inflammasomes, and the mechanisms used by these pathogens to subvert inflammasome functions to promote their survival and sustain infection.…”