Abstract
Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan (PGN)-conserved motifs in cytosol and stimulates host immune response. The association of NOD2 mutations with a number of inflammatory pathologies, including Crohn disease (CD), Graft-versus-host disease (GVHD), and Blau syndrome, highlights its pivotal role in host–pathogen interactions and inflammatory response. Stimulation of NOD2 by its ligand (muramyl dipeptide) activates pro-inflammatory pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and Caspase-1. A loss of NOD2 function may result in a failure in the control of microbial infection, thereby initiating systemic responses and aberrant inflammation. Because the ligand of Nod2 is conserved in both gram-positive and gram-negative bacteria, NOD2 detects a wide variety of microorganisms. Furthermore, current literature evidences that NOD2 is also able to control viruses’ and parasites’ infections. In this review, we present and discuss recent developments about the role of NOD2 in shaping the gut commensal microbiota and pathogens, including bacteria, viruses, and parasites, and the mechanisms by which Nod2 mutations participate in disease occurrence.
Highlights
The mammalian intestinal tract harbors a community of trillions of bacteria, archaea, fungi, and viruses, which are collectively referred to as the microbiome
We present and discuss recent developments about the role of Nucleotide-binding oligomerization domain 2 (NOD2) in shaping the gut commensal microbiota and pathogens, including bacteria, viruses, and parasites, and the mechanisms by which Nod2 mutations participate in disease occurrence
NOD2 plays a key role in gut–microbe homeostasis by sensing both commensal and pathogenic microbes and modulating toll-like receptors (TLRs) signaling pathways
Summary
The mammalian intestinal tract harbors a community of trillions of bacteria, archaea, fungi, and viruses, which are collectively referred to as the microbiome. Nod2KO mice exhibit an increased bacterial translocation of both gram-positive and gram-negative bacteria and the yeast Saccharomyces cerevisiae This barrier defect is located at Peyer’s patches in the ileum [63]. A bacteria-induced overactivation of the MLCK may increase the number of TGF-β-producing regulatory CD4+ T cells in the colonic lamina propria of Nod2KO mice through the induction of an excessive permeability [67] This reciprocal link between immune cells, intestinal permeability, and microbiota is further evidenced by the fact that endocytosis of commensal bacteria in epithelial cells is dependent on MLCK-activated brush border fanning triggered by IFNγ [68,69]. In addition to its role in the regulation of gut microbiota in normal conditions, NOD2 is involved in the host response against infectious pathogens, including bacteria, viruses, and parasites. The recruitment of RIP2/TAK1 complexes by Nod is consistently required to control bacterial infection and related inflammation (Table 1)
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