Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1β (IL-1β) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-β and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1β production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1β and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.
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We thank F. Maxfield (Weill Cornell Medical College) for Lalistat. Supported by the US National Institutes of Health (R01HL117334 and R01AG032349 to K.J.M.; U24 AI082660 to L.M.S. and K.J.M.; R01 AI079198 to L.M.S.; 5R01HL093262-02 and 1R01HL112661-01 to E.L.; and AI083713 to K.A.F. and E.L.) and the American Heart Association (11POST7400075 to F.J.S.).
A.E.M. is an employee of Isis Pharmaceuticals, a biotechnology company that develops ASO therapies.
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Sheedy, F., Grebe, A., Rayner, K. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 14, 812–820 (2013). https://doi.org/10.1038/ni.2639
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