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  • Review Article
  • Published:

Innate immune mechanisms of colitis and colitis-associated colorectal cancer

Key Points

  • Through crosstalk with the intestinal microbiota, the innate immune system regulates intestinal homeostasis by conditioning the immune response both at mucosal sites and systemically, and by providing instructive signals that drive intestinal epithelial cell turnover and mucosal regeneration. The innate immune system is also a crucial modifier of bacterial handling through autophagy and a determinant of intestinal epithelial cell survival and apoptosis.

  • Although excessive Toll-like receptor (TLR) activation in the gut is pathogenic, sensing of the commensal flora by these receptors, particularly TLR2 and TLR4, is required for intestinal homeostasis and control of tissue repair. In addition, apical TLR9 stimulation triggers mucosal tolerance through induction of type I interferons that have been proposed to protect from colonic inflammation.

  • Nucleotide-binding oligomerization domain (NOD) receptors have a paramount role in intestinal homeostasis, and genetic mutations and single-nucleotide polymorphisms (SNPs) in their genes are associated with Crohn's disease. It is generally accepted that alterations in NOD2 function affect susceptibility to IBD because of the key role of this receptor in linking innate signals to the induction of adaptive immune tolerance to the intestinal microbiota. NOD2 modulates TLR signalling, regulates the production of defensins and IL-10, and polarizes the adaptive immune response towards a TH2-type response. More recently, NOD2 was shown to trigger autophagy in response to bacterial sensing through an interaction with the autophagy protein ATG16L1 (autophagy-related 16-like 1).

  • Genetic studies of Crohn's disease, including genome-wide association studies, uncovered two autophagy loci — ATG16L1 and IRGM — that are linked to Crohn's disease susceptibility. Deficiency in ATG16L1 function not only affects the ability of NOD2 to trigger autophagy, but also affects Paneth cells and renders macrophages hyperresponsive to TLR agonists, which leads to excessive inflammasome activation. This suggests that aberrant bacterial handling could act as a trigger for inflammation in Crohn's disease.

  • A SNP in the human NOD-, LRR- and pyrin domain-containing 3(NLRP3) region that downregulates NLRP3 expression is associated with Crohn's disease susceptibility. Consistently, the NLRP3 inflammasome–caspase 1–IL-18–IL-18R–MYD88 axis of inflammation is required for tissue repair following injury and is protective from colitis and colitis-associated colorectal cancer in mouse models.

  • Negative regulators of innate immunity pathways, including SIGIRR (single immunoglobulin IL-1-related receptor), SOCS1 (suppressor of cytokine signalling 1) and caspase 12, are important effectors of intestinal immune tolerance. Deletion of their respective genes leads to amplification of the intestinal inflammatory response and promotion of colorectal cancer.

Abstract

The innate immune system provides first-line defences in response to invading microorganisms and endogenous danger signals by triggering robust inflammatory and antimicrobial responses. However, innate immune sensing of commensal microorganisms in the intestinal tract does not lead to chronic intestinal inflammation in healthy individuals, reflecting the intricacy of the regulatory mechanisms that tame the inflammatory response in the gut. Recent findings suggest that innate immune responses to commensal microorganisms, although once considered to be harmful, are necessary for intestinal homeostasis and immune tolerance. This Review discusses recent findings that identify a crucial role for innate immune effector molecules in protection against colitis and colitis-associated colorectal cancer and the therapeutic implications that ensue.

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Figure 1: Innate immune effector molecules function in IECs to maintain intestinal homeostasis.
Figure 2: Proposed mechanisms of NOD2 function in intestinal homeostasis.
Figure 3: The inflammasome–caspase 1–IL-18–IL-18R–MYD88 axis mediates tissue repair in the intestine.
Figure 4: A dual role for innate immunity in colitis-associated colorectal cancer and intestinal malignancy.

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Acknowledgements

M.S. thanks the students and colleagues in her laboratory for reading and commenting on this manuscript. Work in M.S.'s laboratory is supported by the Canadian Institutes for Health Research (MOP-79410, MOP-82801, MOP-86546, CTP-87520) and the Burroughs Wellcome Fund. Work in G.T.'s laboratory is supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research, USA.

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Glossary

Helminth therapy

Helminth therapy is a form of immunotherapy aimed at modulating the T helper 1 (TH1)/TH2 immune balance. It involves the deliberate inoculation of patients suffering from immune-mediated inflammatory diseases with helminth (parasitic intestinal nematodes) or helminth larvae. The currently studied regimens in humans use Trichuris suis, which does not cross the intestinal barrier or cause an invasive infection.

Autophagy

A tightly regulated catabolic process that involves degradation of the cell's own intracellular components through the lysosomal machinery. It is a normal part of cell growth, development and homeostasis, and recently it has emerged as an efficient innate immunity mechanism.

Villi

Villi are projections into the intestinal lumen. Their outer epithelial layer consists mainly of mature, absorptive enterocytes but also contains mucus-secreting goblet cells.

Crypts

Crypts are tubular invaginations of the intestinal epithelium. At the base of the crypts are Paneth cells, which produce bactericidal defensins, and stem cells, which continuously divide and are the source of all intestinal epithelial cells.

Tight junction

A ring of proteins that seals apical epithelium; these proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludins proteins.

Lamina propria

The connective tissue that underlies the mucosal epithelium and contains various myeloid and lymphoid cells, including macrophages, dendritic cells, B cells and T cells.

Wnt pathway

A signalling pathway that regulates cell fate determination, proliferation, adhesion, migration and polarity during development. In addition to the crucial role of this pathway in embryogenesis, Wnt ligands and their downstream signalling molecules have been implicated in tumorigenesis and have causative roles in human colon cancers.

Adenomatous polyposis coli

(APC). A scaffold protein that sequesters β-catenin in the cytoplasm of resting cells. APC mutations, which are found in 90% of intestinal cancers, lead to constitutively active β-catenin.

Inflammasome

A large multiprotein complex formed by a NOD- and LRR-containing (NLR) protein, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC; also known as PYCARD) and pro-caspase 1. The assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-interleukin-1 β (pro-IL-1β) and pro-IL-18 to generate the active pro-inflammatory cytokines.

Pyroptosis

A form of cell death that is distinct from immunologically silent apoptosis. It is triggered concomitantly with the activation of the inflammasome and requires caspase 1 activity. During pyroptotic cell death, an inflammasome complex forms to activate caspase 1.

ApcMin/+ mice

A mouse strain that carries a point mutation in one adenomatous polyposis coli (Apc) allele and spontaneously develops intestinal adenomas. It is used as a model for human familial adenomatous polyposis and for human sporadic colorectal cancer.

Tumour immunosurveillance

Tumour immunosurveillance or attack refers to the identification and elimination of cancerous or pre-cancerous cells by the immune system. However, as tumours do still develop despite a functioning immune system, the concept of 'immune editing' has taken over.

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Saleh, M., Trinchieri, G. Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat Rev Immunol 11, 9–20 (2011). https://doi.org/10.1038/nri2891

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