Abstract 369: Cd36 Sensing of Metabolic Danger Signals is a Common Mechanism of Nlrp3 Inflammasome Activation

Abstract

Atherosclerosis and type 2 diabetes (T2D) are associated with low-grade systemic inflammation characterized by increased expression of cytokines, particularly interleukin-1β (IL-1β), yet the molecular mechanisms of immune activation remain unclear. Recent studies identified cholesterol crystals and the fibrillar proteins Aβ and IAPP as novel activators of the NLRP3 inflammasome in atherosclerosis, Alzheimer’s disease and T2D, respectively. Notably, the scavenger receptor CD36 has also been implicated in these sterile inflammatory conditions. We now show that CD36 binding of soluble endogenous ligands that accumulate in these diseases (oxLDL, soluble Aβ and IAPP) initiates cooperative signaling via the newly described TLR4/TLR6 heterodimer to prime the inflammasome, including induction of Il1α, IL1β and Nlrp3 mRNAs. Importantly, the unregulated ligand uptake characteristic of CD36 promotes the intracellular formation of inflammasome activators by transforming these soluble ligands into crystalline or fibrillar danger signals. Using combined confocal reflectance microscopy we show that whereas WT macrophages incubated with oxLDL exhibit intracellular crystal formation and lysosomal rupture, these pathologic events are absent in Cd36-/- macrophages. Furthermore, atherosclerotic Apoe-/- mice lacking Cd36 are protected from plaque cholesterol crystal accumulation, caspase-1 activation and serum IL-1β elevation. Via an analogous mechanism, CD36 uptake of soluble Aβ or IAPP leads to intracellular thioflavin-positive fibril formation, lysosomal disruption and inflammasome activation. These findings indicate a shift from the current paradigm that such endogenous crystalline/fibrillar ligands are generated extracellularly and identify CD36-mediated ligand uptake as a shared mechanism by which the NLRP3 inflammasome is triggered in metabolic diseases.