Inflammasomes and intestinal homeostasis: regulating and connecting infection, inflammation and the microbiota

Abstract

Inflammasomes are large cytosolic protein complexes that detect infection and stress-associated signals and promote immediate inflammatory responses. In the intestine, activation of the inflammasome leads to an inflammatory response that is important for controlling enteric infections but can also result in pathological tissue damage. Recent studies have suggested that the inflammasome also regulates intestinal homeostasis through its effects on the intestinal microbiota. Notably, many conflicting studies have been published regarding the effect of inflammasome deficiencies on intestinal homeostasis. Here, we attempt to reconcile these contrasting data by highlighting the many ways that the inflammasome contributes to intestinal homeostasis and pathology and exploring the potential role of alterations in the microbiota in these conflicting studies.

Keywords: IBD; infection; inflammasome; intestine; microbiota.

Fig. 1.

Schematic overview of inflammasome formation. Following a cytosolic stimulus, inflammasome complexes are assembled via homotypic domain–domain interactions, resulting in the autoproteolytic activation of Caspase-1 and the processing and subsequent secretion of IL-1β and IL-18. Protease, proteolytic domain; PYR, pyrin domain.

Fig. 2.

Triangle offense: inflammasome, microbiota and inflammation in DSS-mediated colitis. In mice harboring a ‘healthy’ microbiota, inflammasome-mediated inflammation can exacerbate DSS-mediated colitis (e.g. through the regulation of cytokine secretion); accordingly, inflammasome-deficient mice or mice treated with inflammasome inhibitors have been shown to exhibit reduced DSS-mediated colitis. However, inflammasome-deficient mice in some colonies have been found to harbor a communicable dysbiosis, which is characterized by the presence of Prevotellaceae species. In contrast to inflammasome-deficient mice with a healthy microbiota, dysbiotic inflammasome-deficient mice exhibit hypersensitivity to DSS-mediated colitis. Therefore, inflammasomes may play a dual role in intestinal inflammation—they can drive pathological inflammation in the intestine through the regulation of inflammatory cytokines but may also support the clearance of potentially pathogenic bacterial species.