NOD2 encodes an intracellular multidomain pattern recognition receptor that is the strongest known genetic risk factor in the pathogenesis of Crohn disease (CD), a chronic relapsing inflammatory disorder of the intestinal tract.
Previously, the majority of reviews on NOD2 function have focused upon the role of NOD2 in inflammatory disease or in its interaction with and response to microbes.
This article reviews the role that the NOD2:RIP2 complex plays in inflammatory disease, with an emphasis on the inhibition of this signaling pathway as a novel pharmaceutical target in inflammatory disease.
These findings suggest that ITCH helps regulate NOD2-dependent signal transduction pathways and, as such, may be involved in the pathogenesis of NOD2-mediated inflammatory disease.
Crohn's disease is a prototypical inflammatory disorder in which this process may be faulty as the major Crohn's disease-associated protein, NOD2 (nucleotide oligomerization domain 2), regulates the formation of K63-linked polyubiquitin chains on the I kappa kinase (IKK) scaffolding protein, NEMO (NF-kappaB essential modifier).
With the recent discovery of NOD2 as the first susceptibility gene linked with Crohn's disease, research is now focused on attempting to explain the biological role of NOD2 and how mutations can contribute to the development of this inflammatory disease.
Conversely, mutations in the NBS region of Nod2 induce a constitutive activation of NF-kappaB and are responsible for Blau syndrome, another auto-inflammatory disease.
In contrast, CARD15 alleles associated with Blau's syndrome promoted PGN-independent NF-kappaB activation, an observation that accounts for the minimal microbial input in the etiology of this dominant, monogenic inflammatory disorder affecting solely aseptic sites.
Notably, genetic variation in the genes encoding the NOD proteins NOD2, cryopyrin and CIITA (MHC class II transactivator) in humans and Naip5 (neuronal apoptosis inhibitory protein 5) in mice is associated with inflammatory disease or increased susceptibility to bacterial infections.
Thus, Nod2 expression is enhanced by proinflammatory cytokines and bacterial components via NF-kappaB, a mechanism that may contribute to the amplification of the innate immune response and susceptibility to inflammatory disease.