Enigma of Inflammasome Activation by Kinases.

Abstract

Inflammasomes are large multiprotein complexes composed of signal sensing platform proteins (eg, NLRP3 [NOD-, LRR (leucine-rich repeat)-, and pyrin domaincontaining 3], AIM2 [absent in melanoma 2], and NLRC4 [NLR (NOD-like receptor) family CARD (caspase activation and recruitment domain) domain containing 4]), adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), and effector protein caspase-1. These complexes serve as signaling platforms that activate caspase-1, which in turn cleaves and processes inflammatory cytokines such as IL (interleukin)-1β and IL-18 and triggers the inflammatory response. Active caspase-1 also cleaves the pore-forming protein gasdermin D and generates the aminoterminal fragment, which oligomerizes and forms membrane pores in the plasma membrane, resulting in potassium efflux and pyroptosis. The subsequent potassium efflux leads to further NLRP3 activation.1 By inducing the robust inflammatory response and pyroptotic cell death, the inflammasome cascade contributes to tissue inflammation and destruction in many cardiovascular diseases including atherosclerosis. Thus, better understanding of the regulation of inflammasome and identification of the molecules responsible for inflammasome activation are critical for developing effective therapies to treat diseases in which activation of inflammasome is critically involved.