Validated ligands to modulate NOD1, NOD2, and inflammasome activation
NOD-like receptors (NLRs) are intracellular pattern recognition receptors characterized by a nucleotide-binding and oligomerization (NOD/NACHT) domain and ligand-recognizing leucine-rich repeats (LRRs). They detect pathogen- and danger-associated molecular patterns (PAMPs and DAMPs) to initiate key innate immune responses.
Within this family, NOD1 and NOD2 act as cytosolic sensors of bacterial peptidoglycan fragments, key microbial PAMPs that signal infection. NOD1 recognizes γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) motifs mainly present in Gram-negative and some Gram-positive bacteria, whereas NOD2 detects muramyl dipeptide (MDP) found in virtually all bacterial peptidoglycans. Their activation triggers NF-κB and MAPK signaling cascades, leading to the expression of pro-inflammatory and antimicrobial genes
Inflammasome-forming NLRs, including NLRP1, NLRP3, and NLRC4, are activated by a wider variety of microbial and endogenous stimuli. These include viral components, bacterial toxins and flagellin secretion systems, extracellular ATP, ion fluxes, and crystalline substances. Upon activation, they assemble into multiprotein inflammasome complexes that recruit and activate caspase-1, resulting in IL-1β/IL-18 maturation and pyroptotic cell death.
