Nod-like receptors in the control of intestinal inflammation

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The Nod-like receptor (NLR) family of intracellular pattern recognition molecules plays critical roles in the control of inflammation through the modulation of different signalling pathways, including those dependent on NF-κB and caspase-1-mediated cleavage of interleukin (IL)-1β and IL-18. A number of NLRs or NLR-associated proteins have been genetically associated with susceptibility to inflammatory bowel disease (IBD), either Crohn's disease or ulcerative colitis. Accordingly, recent studies have examined the role of NLR proteins in chemical-induced or bacteria-induced murine models of colitis. In this review, we will discuss the genetic associations of NLRs with IBD and the research using NLR-deficient mice in different colitis models.

Highlights

NLR proteins have been genetically associated with and studied in models of IBD. ► Mice deficient for specific NLRs are susceptible to bacterial and chemical colitis. ► NLR proteins are important mediators between the host and the resident microbiota. ► NLR proteins control innate cytokine responses and cellular proliferation.

Introduction

Nod-like receptors (NLRs) represent a family of cytosolic pattern recognition molecules that trigger inflammatory signalling following detection of either microbial or danger-associated molecular patterns (MAMPs or DAMPs, respectively). These proteins share a common domain organization with a C-terminal leucine-rich repeat (LRR) domain, which is probably involved in direct or indirect sensing or MAMPs or DAMPs, and a central NACHT/NOD domain (nucleotide binding and oligomerization domain). The N-terminal domain of most NLR proteins is involved in the activation of downstream signalling pathways, such as those dependent on NF-κB or caspase-1-triggered inflammasome cascades (Table 1). Within the Nod subfamily, Nod1 and Nod2 consist of one (for Nod1) or two (for Nod2) N-terminal caspase activating and recruiting domains (CARD), which connect these proteins to the NF-κB and MAP kinase signalling cascades through interactions with the serine-threonine kinase Rip2. The NLRP subfamily is defined by proteins that contain pyrin domains and includes NLRP1-12. These proteins, as well as NLRC4, are involved in inflammasome activation, which leads to caspase-1 mediated cleavage of IL-1β, IL-18 and IL-33 [1].

In the intestine, innate immune signalling must be tightly controlled in order to maintain tolerance to the potentially pro-inflammatory commensal bacteria present in the lumen, while protecting the host against invasion by enteric microbial pathogens. NLR proteins are strategically expressed in the intestine at the front line of the host-microbiota interface. Following the key discovery of Nod2 as the first susceptibility gene for Crohn's disease (CD) in 2001, a number of studies have highlighted both the genetic association of NLRs and inflammatory bowel disease (IBD) susceptibility, and the function of NLR-related pathways in maintaining gut homeostasis, which will be the focus of this review.

Section snippets

Inflammatory bowel disease: genetic associations

CD and ulcerative colitis (UC) together make up IBD. Intestinal inflammation in UC patients is limited to the colonic mucosa, whereas inflammation in CD patients can affect the mucosa, epithelium and mucosal layer throughout the gastrointestinal tract. Susceptibility to CD and UC is determined by genetics [2, 3], as well as a number of environmental factors, including smoking, the gut microbiome and diet. CD and UC have been intensively studied genetically and through genome-wide association

Modelling IBD: murine models of colitis

Currently, no animal model can perfectly mimic the full spectrum of intestinal pathology observed in either CD or UC. However, over the years, both chemically induced and bacterially induced models of colitis have been developed that can exhibit some of the pathogenic hallmarks of IBD. The most commonly used chemical models are the dextran sulphate sodium (DSS) and trinitrobenzene sulfonic acid (TNBS)-induced models, where the chemical insult damages the epithelial layer leading to acute

NLRP12

NLRP12 has been recently shown to function as a negative regulator of innate immune-triggered inflammatory pathways. Accordingly, a recent study reported that NLRP12−/− mice display accelerated weight loss, greater intestinal inflammation and impaired capacity to repair damaged gut tissue after DSS challenge [53]. In the same study, NLRP12−/− mice were found to be more susceptible to CAC, probably as a result of an increased infiltration of inflammatory monocytes and macrophages to the MLN and

Concluding remarks

Accumulating evidence suggest that innate immune signalling at the intestinal mucosa is critical for the maintenance of the integrity of this barrier, the regulation of inflammatory pathways, and homeostatic tolerance of the intestinal microbiota. Pioneering studies using mice genetically invalidated for NF-κB signalling in intestinal enterocytes, or lacking Toll-like receptor signalling highlighted this paradigm [54]. Genetic studies demonstrating a critical link between Nod2 deficiency and CD

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

DJP and SEG are supported by grants from the Canadian Institutes for Health Research (CIHR) to DJP, Burroughs Wellcome Fund to SEG, and the Crohn's and Colitis Foundation of Canada (CCFC) to DJP and SEG. TS and SJR are supported by fellowships from CIHR.

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