NOD2 plays a role as an intracellular sensor of bacterial peptidoglycan structures in three of the main cells types representing the intestinal innate immune compartment, i.e., the dendritic cells, monocytes/macrophages and neutrophils. As dendritic cells are required for activation and polarization of naive CD4+ T cells, all modifications of the functional phenotype of dendritic cells are essential for adaptive responses. NOD2 activation by peptidoglycan monomeric structures modifies the response pattern of dendritic cells.59 One or more programs can be induced in dendritic cells, depending on the type of molecular structures that activate pattern recognition receptors on the surface of or inside dendritic cells.60 Cellular-mediated immunity (Th1, Th17), humoral immunity (Th2, Th9), and/or tolerance (regulatory T cells, Treg) are the cardinal programs induced by means of dendritic cell-induced instruction and activation of naive CD4+ T cells.61 In the case of a functional NOD2 program, the phenotypic profile imprinted by NOD2 activation in human dendritic cells is directed towards Th17 activation59 due to enhanced production of IL-23, IL-1β, and IL-6. Activated Th17 cells produce, e.g., IL-17, IL-21, IL-22, TNF-α, IL-26, and CCL20 and thereby promote immune responses that eradicate extracellular microorganisms (bacteria and fungi) by recruiting (via IL-8) and activating neutrophils (IL-17), as well as challenging the production of antimicrobial peptides (S100A8, S100A9, RegIIβ, RegIIIγ) from murine epithelial cells (IL-22 induced).62 Redundancy at the level of NOD2's modifying attributes seems to exist, as Toll-like receptor 2 (TLR2) also recognizes molecular structures derived from bacterial peptidoglycans, and appears to regulate the dendritic cell phenotype towards Th17 activation in a manner similar to NOD2.63 Moreover, collaboration between NOD2 and TLR2 results in additional enhancement of Th17-directing abilities in dendritic cells,63 and NOD2 deficiency (knockout mouse) has been observed to reduce this phenotypic shift. The functional consequence of mtNOD2 for the dendritic cell phenotype is reduced at IL-23 and IL-1β levels, and a defective IL-17 production from memory T cells.59 Moreover, by use of gene expression arrays it was recently shown that certain antiapoptotic gene products are highly upregulated in mtNOD2 dendritic cells from CD patients, which is in contrast to cells from CD patients with wtNOD2, although cells from both disease subgroups express enhanced levels of these gene products as compared to healthy controls.64
The role of a functional NOD2 in macrophages/monocytes is, like in dendritic cells, to respond to intracellular bacteria (i.e., the MDP component) and mediating the synthesis of proinflammatory molecules, in particular IL-8, IL-6, IL-1β, and TNF-α. In mtNOD2 human macrophages33 and peripheral blood mononuclear cells,17 a diminished proinflammatory response is observed upon MDP stimulation. Additionally, NOD2 has been shown to act negatively on the TLR2-mediated Th1 response in murine macrophages. However, this inhibition is abolished in NOD2 knockout mice directing the response towards an increased Th1 cytokine response.65 These findings are in agreement with the characteristics of an enhanced Th1 response observed in CD.66
In neutrophils, wtNOD2 stimulation by MDP is reported to enhance production of β-defensin (HBD-1 and HBD-2), as well as LL-37, IL-21, TNF-α, and IFN-γ.67 Defective NOD2 signaling in neutrophils has been found to reduce HBD-2, LL-37, IL-21, TNF-α, and IFN-γ,67 thereby implicating a collectively reduced antimicrobial functioning in neutrophils that may further consolidate the significance of the NOD2 sensor in the innate antimicrobial defense program.
Based on the functional roles of NOD2 in guiding the activation of innate immune responses against extracellular bacteria, and the additional improvement of epithelium-derived antimicrobial peptide release, it seems likely that the ability to clear off extracellular bacteria is impaired in cases of NOD2 polymorphisms that result in a lack-of-function phenotype. Such attributes could lead to changes in bacterial colonization patterns in the intestine.