The Molecular Basis of NOD2 Susceptibility Mutations in Crohn's Disease

Nod2 is a member of the NLR family of proteins that initiate inflammatory responses when exposed to ligands derived from bacterial components that gain access to the intra-cellular milieu. It is thus somewhat paradoxical that polymorphisms in the gene that encode NOD2 (CARD15) that lead to impaired NOD2 function, are susceptibility factors in Crohn's disease, a condition marked by excessive inflammatory responses to normal bacterial flora. In a series of studies conducted in our laboratory to better define NOD2 function and to resolve this paradox we showed first that NOD2 activation by its ligand, muramyl dipeptide (MDP), ordinarily down-regulates responses to TLR stimulation and thus cells lacking NOD2 mount increased responses to such stimulation. This fits with the fact that mice bearing a NOD2 transgene and thus having cells with increased NOD2 function display decreased responses to TLR stimulation and are resistant to experimental colitis induction. In further studies to analyze these negative effecrts we showed that pre-stimulation of cells with NOD2 ligand renders them unresponsive to TLR stimulation because such pre-stimulation results in the elaboration of IRF4, an inhibitor of TLR-induced inflammatory pathways. Furthermore, administration of MDP to normal mice induces IRF4 and prevents experimental colitis. These studies strongly suggest that NOD2 polymorphisms are associated with Crohn's disease because they lead to a decrease in the negative regulation of TLR responses occuring in the normal gut and thus a pathologic increase in responses to the normal flora. The finding that MDP administration prevents experimental colitis opens the door to the possibility that such treatment might quell Crohn's disease relapses in patients without NOD2 abnormalities.