The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) or nucleotide-binding domain leucine-rich repeat-containing family of genes plays an important role in the development of innate immune responses. Some family members are known to form multiprotein complexes known as inflammasomes that regulate the processing and secretion of proinflammatory mediators, such as interleukin-1β and interleukin-18. Activity of the inflammasome is triggered not only by microbial infection, but also by a wide range of both exogenous and endogenous noninfectious stimuli. Consequently, the dysregulation of inflammasome activity is associated with numerous proinflammatory, non-microbial human diseases. The discovery of NLRP3 gene mutations in autoinflammatory diseases such as Muckle-Wells syndrome has led to the association of NLRs in the pathogenesis of many non-microbial diseases that include arthritis, neurodegenerative disorders, metabolic disorders (obesity and diabetes), cardiovascular disease (atherosclerosis, myocardial infarction), inflammatory bowel disease, kidney disease and hypersensitivity dermatitis. A number of NLRs are also associated with human disease in the absence of inflammasome activity, suggesting additional roles for NLRs in the regulation of inflammation and disease. This review serves to provide a summary of NLR-associated diseases and, where possible, the mechanisms behind the associations.

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