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Diverging inflammasome signals in tumorigenesis and potential targeting

Nature Reviews Cancer volume 19, pages 197–214 (2019)Cite this article

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Abstract

Inflammasomes are molecular platforms that assemble upon sensing various intracellular stimuli. Inflammasome assembly leads to activation of caspase 1, thereby promoting the secretion of bioactive interleukin-1β (IL-1β) and IL-18 and inducing an inflammatory cell death called pyroptosis. Effectors of the inflammasome efficiently drive an immune response, primarily providing protection against microbial infections and mediating control over sterile insults. However, aberrant inflammasome signalling is associated with pathogenesis of inflammatory and metabolic diseases, neurodegeneration and malignancies. Chronic inflammation perpetuated by inflammasome activation plays a central role in all stages of tumorigenesis, including immunosuppression, proliferation, angiogenesis and metastasis. Conversely, inflammasome signalling also contributes to tumour suppression by maintaining intestinal barrier integrity, which portrays the diverse roles of inflammasomes in tumorigenesis. Studies have underscored the importance of environmental factors, such as diet and gut microbiota, in inflammasome signalling, which in turn influences tumorigenesis. In this Review, we deliver an overview of the interplay between inflammasomes and tumorigenesis and discuss their potential as therapeutic targets.

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Fig. 1: Diverse mechanisms of inflammasome activation.
Fig. 2: Pro-tumorigenic roles of inflammasome components.
Fig. 3: Protective roles of inflammasomes in cancer.
Fig. 4: Inflammasome–microbiota axis in intestinal homeostasis.
Fig. 5: Inflammasome signalling during chemotherapy.

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Acknowledgements

Research studies from our laboratory are supported by the US National Institutes of Health (AR056296, CA163507, AI124346 and AI101935 to T.-D.K.) and the American Lebanese Syrian Associated Charities (to T.-D.K.). The authors apologize to colleagues whose work was not cited owing to space limitations.

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  1. Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Rajendra Karki & Thirumala-Devi Kanneganti

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  1. Rajendra Karki
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Both authors contributed equally to researching data for the article and writing and editing the article.

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Glossary

Gut microbiota

The ecological community of microorganisms harboured in the gastrointestinal tract.

Pyroptosis

An inflammatory and lytic form of cell death mediated by inflammatory caspases.

gp130 F/F mice

A mouse model that is generated using a phenylalanine knock-in substitution at tyrosine 757 in the cytoplasmic domain of the interleukin-6 (IL-6) receptor β-chain (gp130). The mice rapidly develop tumours in the epithelium of the glandular stomach and highlight a key role for signal transducer and activator of transcription 3 (STAT3) signalling in gastric tumorigenesis.

Tumour microenvironment

(TME). The cellular and molecular environment where tumour cells interact with infiltrating immune cells, fibroblasts, blood vessels and extracellular matrix.

Tumour-associated macrophages

(TAMs). A class of mostly abundant immune cells present in the tumour microenvironment. They have a tumour-promoting phenotype via modulating tumour cell proliferation, tumour angiogenesis, invasion and metastasis.

Alarmins

Damage-associated molecular patterns such as high mobility group box 1 (HMGB1) or interleukin-1α (IL-1α) released by damaged or necrotic cells.

Plasmacytoid dendritic cells

(pDCs). A type I interferon-producing subset of dendritic cells with antigen-presenting potential.

Hepatic sinusoidal endothelial cells

(HSECs). A special type of endothelial cells that represent the interface between blood cells on the one side and hepatocytes and hepatic stellate cells on the other side.

Epithelial-to-mesenchymal transition

(EMT). A process by which epithelial cells lose their polarity and cell–cell adhesion properties and acquire mesenchymal fibroblast-like properties.

Matrix metalloproteinases

(MMPs.) A family of endopeptidases capable of degrading extracellular matrix components, influencing multiple cellular processes such as migration and adhesion.

Azoxymethane

(AOM). A potent carcinogen that is used to induce colon carcinoma in mice and rats. It is metabolized to methylazoxymethanol in the liver and then reaches the colon via the bloodstream rather than the bile.

Mucin 2

(MUC2). A glycoprotein that is particularly prominent in the gut and is secreted from goblet cells in the epithelial lining into the lumen of the large intestine.

Nlrp3 R258W mice

Genetically modified mice carrying the R258W mutation in the Nlrp3 gene, which corresponds to the R260W mutation in the NLRP3 gene in humans. These mice develop severe cutaneous lesions, including erythema, scaling and thickening of both the epidermis and the dermis, symptoms that recapitulate urticaria-like skin lesions reported in patients with Muckle–Wells syndrome.

Deoxycholic acid

A bile acid that emulsifies and solubilizes dietary fats in the intestine.

Crohn’s disease

An inflammatory bowel disease that involves chronic inflammation of the digestive tract.

Familial Mediterranean fever

(FMF). Mutations in the gene encoding pyrin (MEFV) are associated with FMF, which is an autosomal recessive, autoinflammatory disorder characterized by episodic fever and neutrophil-mediated inflammation of serosal tissues.

Sjögren syndrome

An autoimmune disease that mostly affects the salivary and lacrimal glands, resulting in dry mouth and dry eyes.

Canakinumab Anti-inflammatory Thrombosis Outcomes Study

(CANTOS). A randomized, double-blinded, placebo-controlled trial to evaluate the effect of canakinumab, a human monoclonal antibody that selectively neutralizes interleukin-1β (IL-1β), in the prevention of recurrent vascular events in patients with previous myocardial infarction.

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Karki, R., Kanneganti, TD. Diverging inflammasome signals in tumorigenesis and potential targeting. Nat Rev Cancer 19, 197–214 (2019). https://doi.org/10.1038/s41568-019-0123-y

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