NLRP3

Definition : NACH T, LRR and PYD domains-containing protein 3 (NALP3 ) also known by cryopyrin is a protein that in humans is encoded by the NLRP3 gene located on the long arm of chromosome 1.

NALP3 is expressed predominantly in macrophages and as a component of the inflammasome (" NLRP3 inflammasome " , detects products of damaged cells such as extracellular ATP and crystalline uric acid.

Activated NALP3 in turn triggers an immune response.

Pathology

 The NLRP3 inflammasome has a critical role in NASH and the progression of NAFLD to NASH.

 Mutations in the NLRP3 gene are associated with a number of organ specific autoimmune diseases.

 Mutations in the NLRP3 gene have been associated with a spectrum of dominantly inherited autoinflammatory diseases called cryopyrin-associated periodic syndrome (CAPS). This includes :

• familial cold autoinflammatory syndrome (FCAS)
• Muckle–Wells syndrome (MWS)
• chronic infantile neurological cutaneous and articular (CINCA) syndrome
• neonatal onset multisystem inflammatory disease (NOMID)
• keratoendotheliitis fugax hereditaria

 Defects in this gene have also been linked to familial Mediterranean fever.

 The NALP3 inflammasome has a role in the pathogenesis of gout and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer’s, Parkinson’s, and prion diseases.

 Amelioration of mouse models of many diseases has been shown to occur by deletion of the NLRP3 inflammasome, including gout, type 2 diabetes, multiple sclerosis, Alzheimer’s disease, and atherosclerosis.

 The ketone β-Hydroxybutyrate has been shown to block NLRP3 activation, and thus may be of benefit for many of these diseases.

 Deregulation of NALP3 has been connected with carcinogenesis. For example, all the components of the NALP3 inflammasome are downregulated or completely lost in human hepatocellular carcinoma.

References

 A critical role for the NLRP3 inflammasome in NASH . Nature Reviews Gastroenterology & Hepatology (2017) doi : 10.1038/nrgastro.2017.21