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Review
. 2008;10(6):228.
doi: 10.1186/ar2525. Epub 2008 Nov 25.

NOD-like receptors and inflammation

Rebeccah J Mathews  1 , Michael B Sprakes, Michael F McDermott
Affiliations
Review

NOD-like receptors and inflammation

Rebeccah J Mathews et al. Arthritis Res Ther. 2008.

Abstract

The nucleotide-binding and oligomerization domain, leucine-rich repeat (also known as NOD-like receptors, both abbreviated to NLR) family of intracellular pathogen recognition receptors are increasingly being recognized to play a pivotal role in the pathogenesis of a number of rare monogenic diseases, as well as some more common polygenic conditions. Bacterial wall constituents and other cellular stressor molecules are recognized by a range of NLRs, which leads to activation of the innate immune response and upregulation of key proinflammatory pathways, such as IL-1beta production and translocation of nuclear factor-kappaB to the nucleus. These signalling pathways are increasingly being targeted as potential sites for new therapies. This review discusses the role played by NLRs in a variety of inflammatory diseases and describes the remarkable success to date of these therapeutic agents in treating some of the disorders associated with aberrant NLR function.

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Figures

Figure 1
Figure 1
Species homology between the Toll, TLRs, NLRs and plant resistance (R) proteins. Central to innate immunity are the highly conserved core domains that are found in drosophilae, mammals and plants. The Toll family of proteins share homology in their signalling domains with IL-1RI; this family includes Drosophila Toll, plant R proteins, and mammalian TLRs and NLRs. CARD, caspase activation and recruitment; IL-1RI, type I IL-1 receptor; LRR, leucine rich repeat; NALP1, NACHT, leucine rich repeat and pyrin domain containing 1; NLR, NOD-like receptor; PYD, pyrin domain; TLR, Toll-like receptor.
Figure 2
Figure 2
The NALP1 and NALP3 inflammasome complexes. Both NALP1 and NALP3 associate through homotypic interactions between CARD, ASC and the PYD domains. NALP3 requires a secondary adaptor protein Cardinal to facilitate the activation of caspase-1 and the subsequent cleavage of pro-IL-1, in addition to the adaptor protein ASC. This is not required for the NALP1 inflammasome, which has additional FIIND and CARD domains attached to the core NALP1 protein. ASC, apoptosis-associated speck-like protein; CARD, caspase activation and recruitment; FIIND, domain with a function to find; IL, interleukin; LRR, leucine rich repeat; NALP, NACHT, leucine rich repeat and pyrin domain containing 1; PYD, pyrin domain.
Figure 3
Figure 3
Nodosome signalling. Ligand binding to the LRR region regulates oligomerization of the NACHT domain and homotypic interactions between CARD domains and RIP2. Ubiquitination of the IKK complex following oligomerization of RIP2 allows for nuclear translocation of NF-κB and subsequent upregulation of proinflammatory cytokines. CARD, caspase activation and recruitment; IKK, IκB kinase; LRR, leucine rich repeat; NEMO, NF-κB essential modifier; NF-κ, nuclear factor-κB; RIP, receptor-interacting protein.
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