CD36: linking lipids to the NLRP3 inflammasome, atherogenesis and atherothrombosis

Uptake of the atherogenic lipid mediator oxLDL by CD36 results in the formation of intracellular cholesterol crystals that caused lyso¬somal destabilization and NLRP3 activation. oxLDL not only primes, via a NF-κB-dependent pathway, but also activates NLRP3. CD36-mediated inflammasome activation provides an early pathogenic pathway that links cholesterol accumulation to the chronic inflammatory process of atherosclerosis. During atherogenesis, activated or injured endothelial cells, leucocytes and platelets release ATP that acts in a paracrine manner to transduce sterile inflammatory signals. Among these signals, P2X7 receptors mediate K+ efflux leading to NLRP3 activation. Since ATP assembles ASC complexes in oxLDL-treated macrophages, P2X7 receptors and CD36 may cooperate in vivo to activate NLRP3 inflammasome, contributing to plaque formation. Besides macrophages, CD36 is expressed on platelets where it mediates oxLDL-dependent platelet activation and potentially further IL-1β release. P2X7 receptors contributes to protein disulfide isomerase (PDI) tissue factor-dependent thrombosis. Consequently, both CD36 and P2X7 receptors may be involved in atherothrombosis upon plaque rupture.