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  • Review Article
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NOD proteins: regulators of inflammation in health and disease

Nature Reviews Immunology volume 14, pages 9–23 (2014)Cite this article

Subjects

A Corrigendum to this article was published on 23 December 2013

This article has been updated

Key Points

  • NOD1 (nucleotide oligomerization domain-containing protein 1) and NOD2 are members of the NOD-like receptor family of proteins, which function to detect peptidoglycan and to stimulate host responses to limit bacterial infection. The link between NOD2 and the inflammatory bowel disease Crohn's disease highlights the importance of maintaining balanced innate immune responses through NOD signalling in response to the host microbiota at the intestinal mucosa.

  • NOD proteins react to peptidoglycan fragments that enter into the host cytosol by a variety of mechanisms, including direct infection by cyto-invasive pathogens, delivery through bacterial outer membrane vesicles or type IV secretion systems, and through membrane oligopeptide transporters, including solute carrier family 15 member 4 (SLC15A4) and pH-sensing regulatory factor of peptide transporter 1 (PEPT1). Fragments of peptidoglycan can bind to NOD1 and NOD2, inducing their self-association through their interaction at the nucleotide-binding domain (NBD). Oligomerization leads to the recruitment of receptor-interacting protein 2 (RIP2), which regulates the activation of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways.

  • NOD signalling results in several downstream effects, including cytokine production, recruitment of neutrophils and inflammatory macrophages, and initiation of type 2 immunity. Mice that are deficient in the NOD signalling pathway have altered abilities to fight off bacterial infection. Interestingly, several pathogens have developed mechanisms to evade NOD-mediated immunity, including mechanisms that modify peptidoglycan.

  • Autophagy is also affected by NOD signalling. NOD proteins mediate the detection of bacteria, such as Shigella flexneri, in the cytosol of infected cells and, through their interaction with a key autophagy protein called ATG16L1 (autophagy-related protein 16-like 1), can bring the autophagy machinery to the site where the bacteria reside in the cytosol. The induction of autophagy wraps cytosolic bacteria in autophagosomes that subsequently fuse with lysosomes to degrade the bacteria. The interaction of ATG16L1 with NOD1 and NOD2 also regulates the ability of the NODs to drive inflammatory signalling. Indeed, ATG16L1 is a negative regulator of NOD signalling and reduces cytokine production in a manner that is independent of autophagy.

  • Most studies using mouse colitis models have shown that NODs have a protective role in intestinal inflammation. NODs maintain intestinal homeostasis by a variety of mechanisms including fortification of the intestinal barrier and regulation of early inflammatory pathways, such as those governed by interleukin-17 (IL-17), to limit infection and to promote mucosal healing. NOD signalling is also thought to influence the gut microbiota, although there is still controversy as to whether NOD deficiency itself or the underlying inflammation mediates changes in the gut microbial communities.

  • NOD proteins also affect the development of extra-intestinal diseases and cancer. Polymorphisms in the genes that encode NOD1 and NOD2 have been linked to asthma and atopy, graft-versus-host disease, the auto-inflammatory disease Blau syndrome, and cancer. In the case of cancer, NOD deficiency promotes carcinogenesis by providing an inflammatory microenvironment that is exacerbated by chemicals, such as dextran sodium sulphate (DSS), that induce epithelial injury.

Abstract

Entry of bacteria into host cells is an important virulence mechanism. Through peptidoglycan recognition, the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 enable detection of intracellular bacteria and promote their clearance through initiation of a pro-inflammatory transcriptional programme and other host defence pathways, including autophagy. Recent findings have expanded the scope of the cellular compartments monitored by NOD1 and NOD2 and have elucidated the signalling pathways that are triggered downstream of NOD activation. In vivo, NOD1 and NOD2 have complex roles, both during bacterial infection and at homeostasis. The association of alleles that encode constitutively active or constitutively inactive forms of NOD2 with different diseases highlights this complexity and indicates that a balanced level of NOD signalling is crucial for the maintenance of immune homeostasis.

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Figure 1: Tripartite structure of NOD1 and NOD2.
Figure 2: NOD1 and NOD2 localization during infection and ligand recognition.
Figure 3: NOD1 and NOD2 stimulation drives autophagosome formation.
Figure 4: Role of NOD2 in Crohn's disease.

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Change history

  • 23 December 2013

    In the original article the name of the author Susan J. Robertson was mispelled. This error has now been corrected online.

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Acknowledgements

D.J.P., S.E.G. and K.C. acknowledge funding support from the Crohn's and Colitis Foundation of Canada, the Canadian Institutes of Health Research (CIHR) and the Canadian Association for Gastroenterology for their research discussed in this Review. M.T.S. is supported by a Canadian Graduate Scholarship – Doctoral fellowship from the CIHR and a CIHR Strategic Training Fellowship (STP-53877). S.J.R. is supported by a fellowship from the CIHR, the Canadian Association for Gastroenterology and Janssen.

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  1. Dana J. Philpott, Matthew T. Sorbara and Stephen E. Girardin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, University of Toronto, Toronto, M5S 1A8, Canada

    Dana J. Philpott, Matthew T. Sorbara & Susan J. Robertson

  2. Department of Medicine, Institute of Medical Science, University of Toronto, Toronto, M5S 1A8, Canada

    Kenneth Croitoru

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M5S 1A8, Canada

    Stephen E. Girardin

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PowerPoint slides

Glossary

Microorganism-associated molecular patterns

(MAMPs). Highly conserved molecular determinants that are specific to microorganisms and that are detected by the host innate immune system.

Peptidoglycan

A heterogeneous polymer found in the cell wall of bacteria, comprising repeating units of N-acetylglucosamine and N-acetylmuramic acid, which form chains that are held together by short peptides. Immunostimulatory fragments of peptidoglycan can be released that drive the activation of NOD1 and NOD2.

Paneth cells

Highly specialized cells found at the base of the intestinal crypts, which produce abundant amounts of antimicrobial peptides, probably to protect adjacent intestinal stem cells from infection.

Butyrate

A short-chain fatty acid, which is generated by the microbial fermentation of dietary substrates and which is produced in the colon and may influence colonic disease.

Bacterial secretion systems

Complex molecular structures in the shape of a needle that are assembled by bacteria to deliver effectors directly from the bacterial cytoplasm to the host cell.

Outer membrane vesicles

(OMVs). Vesicles between 0.1 and 1 μm in length that bud from the outer membrane of Gram-negative bacteria and that contain a range of microorganism-associated molecular patterns, including cell wall components and bacterial DNA, which can activate host innate immunity.

TNBS-induced colitis

A model of hapten-induced colitis that is induced following intrarectal delivery of 2,4,6-trinitrobenzene sulphonic acid (TNBS), which induces a T cell-driven inflammation.

ATG16L1

(Autophagy-related protein 16-like 1). A crucial part of the macroautophagy machinery. ATG16L1 interacts with a conjugate of ATG5–ATG12 to drive the conjugation of phosphotidylethanolamine to LC3, forming LC3-II — a key step in autophagosome formation. ATG16L1 functions to determine the site of LC3-II formation.

Autophagy

A cytoplasmic bulk degradation system in which cytoplasmic cargo is targeted and sequestered in double-membrane vesicles, leading to subsequent fusion with the lysosome. This process is essential for the response to starvation because it facilitates the recycling of cellular components. In addition, autophagy can be targeted to intracellular bacteria to restrict their growth.

Blau syndrome

A rare familial inflammatory disorder that primarily affects the skin, joints and eyes, and that is caused by gain-of-function mutations in NOD2.

Early-onset sarcoidosis

A sporadic multi-organ inflammatory disorder that has a similar genetic aetiology to Blau syndrome (that is, it is characterized by gain-of-function mutations in NOD2), which typically manifests before the age of 4 years.

Dysbiosis

A condition in which the balance of the bacterial communities that constitute the intestinal microbiota is altered, which could represent a predisposition factor for several diseases.

Dextran sodum sulphate-induced colitis

(DSS-induced colitis). A model of colitis that is induced by oral administration of the chemical irritant DSS to drinking water, which results in epithelial erosion and intestinal inflammation.

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Philpott, D., Sorbara, M., Robertson, S. et al. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol 14, 9–23 (2014). https://doi.org/10.1038/nri3565

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