Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis

Abstract

Inflammasome signalling is an emerging pillar of innate immunity and has a central role in the regulation of gastrointestinal health and disease. Activation of the inflammasome complex mediates both the release of the pro-inflammatory cytokines IL-1β and IL-18 and the execution of a form of inflammatory cell death known as pyroptosis. In most cases, these mediators of inflammation provide protection against bacterial, viral and protozoal infections. However, unchecked inflammasome activities perpetuate chronic inflammation, which underpins the molecular and pathophysiological basis of gastritis, IBD, upper and lower gastrointestinal cancer, nonalcoholic fatty liver disease and obesity. Studies have also highlighted an inflammasome signature in the maintenance of gut microbiota and gut–brain homeostasis. Harnessing the immunomodulatory properties of the inflammasome could transform clinical practice in the treatment of acute and chronic gastrointestinal and extragastrointestinal diseases. This Review presents an overview of inflammasome biology in gastrointestinal health and disease and describes the value of experimental and pharmacological intervention in the treatment of inflammasome-associated clinical manifestations.

Abstract

Inflammasome signalling has a central role in the regulation of gastrointestinal health and disease. Here, an overview of inflammasome biology in relation to the gastrointestinal tract is presented, with insights into how targeted interventions might be useful to treat inflammasome-mediated gastrointestinal diseases

Key points

• Inflammasomes are expressed in both immune and non-immune cells, contributing to their functional ties to infection, IBD, cancer, autoinflammation and autoimmune conditions.

• Inflammasome sensors function by recognizing and responding to a pathogen (lipopolysaccharide, microbial DNA or bacterial flagellin) or to a danger signal (ion flux, self-DNA or ATP).

• Inflammasomes control the magnitude of inflammation and cell death in response to pathogen-associated molecular patterns or danger-associated molecular patterns, which, in part, determines a protective or detrimental outcome in the host.

• Experimental and pharmacological interventions have yielded success in the treatment of inflammasome-mediated disorders, such as autoinflammatory enterocolitis.

• The inflammasome–gut microbiota axis and its relevance to health and disease are influenced by genetic, environmental and experimental factors.

• The deep and complex relationship between inflammasomes, pathogens and the microbiota provides an exciting platform for basic and clinical research with which to understand health and disease.