Nod2: a key regulator linking microbiota to intestinal mucosal immunity

Abstract

The human intestine harbors a large number of bacteria that are constantly interacting with the intestinal immune system, eliciting non-pathological basal level immune responses. Increasing evidence points to dysbiosis of microbiota in the intestine as an underlying factor in inflammatory bowel disease susceptibility. Loss-of-function mutations in NOD2 are among the stronger genetic factors linked to ileal Crohn's disease. Indeed, Nod2 is a key regulator of microbiota in the intestine, as microflora in the terminal ileum is dysregulated in Nod2-deficient mice. Nod2 is highly expressed in Paneth cells, which are responsible for the regulation of ileal microflora by anti-microbial compounds, and Nod2-deficient ileal intestinal epithelia are unable to kill bacteria efficiently. It is therefore likely that NOD2 mutations in Crohn's disease may increase disease susceptibility by altering interactions between ileal microbiota and mucosal immunity.

Figure 1

MDP-induced Nod2 signaling pathway. Enzymatic breakdown of bacterial cell wall peptidoglycan in the phagolysosome may generate active moieties including muramyl dipeptide (MDP), which is recognized by NOD2 through the leucine-rich repeat (LRR). NOD2 recruits RIP2 kinase through CARD-CARD interactions and RIP2 subsequently activates the IKK complex resulting in phosphorylation, ubiquitination and degradation of IκB, and nuclear translocation of NF-κB transcription factors. NOD2 activation also results in the activation of MAP kinase pathways through RIP2. These signaling cascades result in the induction of various immune response gene such as proinflammatory cytokines and defensins.

Figure 2

Inter-regulation of Nod2 and commensal bacteria in the gut. A) Expression of Nod2 in ileal Paneth cells with reduced bacterial flora or in the absence of commensal bacteria (as in germ free mice) is low (left panel), but its expression is induced by bacterial colonization of the gut mucosa (right panel). B) In the presence of functional Nod2, Paneth cells sense the presence of bacteria or bacterial antigen and release anti-microbial peptides, which keep the intestinal flora in check and aid in maintaining homeostasis (left panel). Deletion of Nod2 or the presence of a Nod2 “loss of function” mutation renders Paneth cells nonfunctional. Lack of Paneth cell-derived anti-bacterial compounds leads to unchecked bacterial colonization of the intestinal mucosa and breakdown of homeostasis (right panel).