NOD-like receptors and inflammasomes: A review of their canonical and non-canonical signaling pathways

The NOD-like receptor (NLR) family of proteins is a group of pattern recognition receptors (PRRs) known to mediate the initial innate immune response to cellular injury and stress. The NLRP proteins represent a fourteen-member subset of the NLR family that contains an N-terminal pyrin domain. Some NLRs are known to form multi-protein complexes known as inflammasomes. Inflammasomes consist of an NLR, the adaptor protein ASC, and the effector molecule pro-caspase-1. Once activated, these inflammasomes facilitate the cleavage and activation of caspase-1, which in turn mediates the cleavage of the pro-inflammatory cytokines IL-1β and IL-18 into their active and secreted forms. Activated caspase-1 also drives the cleavage of gasdermin D, which triggers an inflammatory form of cell death known as pyroptosis. Several NLRs are also known to possess non-canonical, inflammasome-independent functions, regulating a variety of signaling pathways. In this review, a thorough overview of both inflammasome-dependent and -independent NLR signaling will be presented, with highlights from the field as well as promising future directions and postulates based on the known science.