Probably the most well-known receptors of peptidoglycan are the NOD-like receptors (NLRs), mainly NOD1 and NOD2. The NOD1 receptor is activated after iE-DAP (γ-d-glutamyl-meso-diaminopimelic acid) binding, while NOD2 recognizes MDP (muramyl dipeptide), by their LRR domains. Activation leads to self-oligomerization, resulting in activation of two signalling cascades. One triggers activation of NF-κB (through RIP2, TAK1 and IKK), second leads to MAPK signalling cascade. Activation of these pathways induces production of inflammatory cytokines and chemokines.
NOD1 is expressed by diverse cell types, including myeloid phagocytes, epithelial cells and neurons. NOD2 is expressed in monocytes and macrophages, epithelial intestinal cells, Paneth cells, dendritic cells, osteoblasts, keratinocytes and other epithelial cell types. As cytosolic sensors, NOD1 and NOD2 must either detect bacteria that enter the cytosol, or peptidoglycan must be degraded to generate fragments that must be transported into the cytosol for these sensors to function.
Recently, it was demonstrated that NLRP3 is activated by peptidoglycan, through a mechanism that is independent of NOD1 and NOD2. In macrophages, N-acetylglucosamine generated by peptidoglycan degradation was found to inhibit hexokinase activity and induce its release from the mitochondrial membrane. It promotes NLRP3 inflammasome activation through a mechanism triggered by increased mitochondrial membrane permeability.
NLRP1 is also considered as a cytoplasmic sensor of peptidoglycan. It can sense MDP and promote IL-1 secretion through binding NOD2.