Role of NLR Proteins in Innate Immunity and Disease

NOD-like receptors (NLRs) are members of a family of cytosolic proteins with structural homology to the apoptosis activator Apaf-1 and plant disease resistance (R) gene products. NLRs contain variable N-terminal effector domains, a centrally located nucleotide-binding oligomerization domain (NOD) and C-terminal leucine-rich repeats (LRRs). NLRs mediate recognition of conserved microbial structures through their LRRs and upon activation induce multiple defense signaling pathways. Nod1 and Nod2 sense conserved, but distinct structural motifs, in bacterial peptidoglycan while Ipaf and Cryopyrin sense cytosolic flagellin and microbial RNA, respectively. Cryopyrin/Nalp3 and Ipaf are critical for the activation of inflammasomes, molecular platforms that mediate the activation of caspase-1 and processing of pro- IL-1β/IL-18 into mature IL-1β and IL-18 in response to intracellular bacteria. Mutations in Nod2 are associated with Crohn's disease whereas Cryopyrin/Nalp3 are linked to several autoinflammatory syndromes that are characterized by inappropriate l secretion of IL-1β. Genetic and biochemical analyses revealed that cytosolic NLR proteins activate host signaling pathways independently of TLR signaling, although both NLRs and TLRs cooperate for optimal immune responses to bacterial pathogens. The results available so far suggest that NLRs are critical mediators of innate immune responses by linking intracellular recognition of bacteria to signaling pathways and their deregulation play an important role in inflammatory disease.