Nodlike

NOD-like receptors, or NLRs, are intracellular pattern recognition receptors of the innate immune system that detect bacterial, viral, and cellular stress signals. They respond to pathogen-associated and danger-associated molecular patterns and regulate inflammation, autophagy, and cell death.

NLRs share a conserved architecture that includes a central NACHT (NOD) domain required for oligomerization, a C-terminal leucine-rich repeat (LRR) domain for sensing ligands, and an N-terminal effector region that varies among family members (CARD in some, PYD in others). Based on these domains, they are grouped into subfamilies such as NLRA, NLRB, NLRC, and NLRP, plus NAIPs.

The best-characterized NOD-like receptors NOD1 and NOD2 detect peptidoglycan fragments, iE-DAP and muramyl dipeptide respectively. Upon sensing ligands, they recruit the kinase RIPK2 via CARD-CARD interactions, leading to activation of NF-κB and MAPK pathways and transcription of inflammatory genes.

Several NLRs, especially the NLRP subfamily, function as inflammasome sensors. They assemble with the adaptor ASC and caspase-1 to process pro-IL-1β and pro-IL-18 into their active forms and can trigger pyroptotic cell death in response to danger signals.

Notable members include NLRP3, NLRP1, NLRC4, NOD1, NOD2, CIITA (NLRA), and NAIPs. They regulate immune responses to pathogens and sterile stress, and influence autophagy and epithelial barrier functions.

Dysregulation or mutations in NLRs are linked to autoinflammatory and autoimmune diseases, including CAPS (NLRP3) and Crohn’s disease (NOD2). Therapeutic approaches target NLR signaling, with NLRP3 inhibitors in development.