{NLRP3} inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases

摘要

IL-1β production is critically regulated by cytosolic molecular complexes, termed inflammasomes. Different inflammasome complexes have been described to date. While all inflammasomes recognize certain pathogens, it is the distinctive feature of {NLRP3} inflammasome to be activated by many and diverse stimuli making {NLRP3} the most versatile, and importantly also the most clinically implicated inflammasome. However, {NLRP3} activation has remained the most enigmatic. It is not plausible that the intracellular {NLRP3} receptor is able to detect all of its many and diverse triggers through direct interactions; instead, it is discussed that {NLRP3} is responding to certain generic cellular stress-signals induced by the multitude of molecules that trigger its activation. An ever increasing number of studies link the sensing of cellular stress signals to a direct pathophysiological role of {NLRP3} activation in a wide range of autoinflammatory and autoimmune disorders, and thus provide a novel mechanistic rational, on how molecules trigger and support sterile inflammatory diseases. A vast interest has created to unravel how {NLRP3} becomes activated, since mechanistic insight is the prerequisite for a knowledge-based development of therapeutic intervention strategies that specifically target the {NLRP3} triggered IL-1β production. In this review, we have updated knowledge on {NLRP3} inflammasome assembly and activation and on the pyrin domain in {NLRP3} that could represent a drug target to treat sterile inflammatory diseases. We have reported mutations in {NLRP3} that were found to be associated with certain diseases. In addition, we have reviewed the functional link between {NLRP3} inflammasome, the regulator of cellular redox status Trx/TXNIP complex, endoplasmic reticulum stress and the pathogenesis of diseases such as type 2 diabetes. Finally, we have provided data on {NLRP3} inflammasome, as a critical regulator involved in the pathogenesis of obesity and cardiovascular diseases.