NOD-like Receptors and the Inflammasome

NOD-like Receptors (NLRs) are a subset of pattern recognition receptors (PRRs) found in the cytosol that are essential for detecting invading pathogens and initiating the innate immune response. The NLR family consists of twenty-two human proteins and at least thirty-four mouse proteins that are divided into subfamilies based on their N-terminal protein-interacting domains. All NLRs also contain a central nucleotide-binding/oligomerization domain (NACHT) and most have a variable number of ligand-sensing, leucine-rich repeats at their C-terminal ends. NLRs are activated by bacterial, fungal, or viral molecules that contain pathogen-associated molecular patterns (PAMPs) or by nonmicrobial danger signals (DAMPs) released by damaged cells. NOD1 and NOD2 are two well-characterized NLRs belonging to the NLRC subfamily. Upon activation, they homo-oligomerize and recruit signaling molecules that drive the NF-kappa B-/AP-1-dependent expression of pro-inflammatory cytokines. In addition, they stimulate the IRF3-/IRF7-dependent expression of type I interferons.

Other NLRs, including NLRP1, NLRP3, and NLRC4, oligomerize to form multiprotein inflammasome complexes. Inflammasome oligomerization requires two signals, a priming signal that results in the transcription of Pro-IL-1 beta and Pro-IL-18, and a second signal that promotes indirect activation of the inflammasome, such as ion or membrane perturbations, reactive oxygen species (ROS), or extracellular ATP. Inflammasome oligomerization leads to the cleavage and activation of Caspase-1, which promotes the processing and secretion of IL-1 beta and IL-18. Similar to TLR signaling, inflammasome activation is tightly regulated and constitutive inflammasome activation and the overproduction of IL-1 beta and IL-18 have been linked to autoinflammatory and autoimmune disorders.