CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation
Department of Medicine, Division of Infectious Diseases and Immunology
Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease
Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1beta (IL-1beta) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-beta 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-1beta production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1beta 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.
DOI of Published Version
Nat Immunol. 2013 Aug;14(8):812-20. doi: 10.1038/ni.2639. Epub 2013 Jun 30. Link to article on publisher's site
Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, Becker CE, Ediriweera HN, Mullick AE, Golenbock DT, Stuart LM, Latz E, Fitzgerald KA, Moore KJ. (2013). CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Infectious Diseases and Immunology Publications. https://doi.org/10.1038/ni.2639. Retrieved from https://escholarship.umassmed.edu/infdis_pp/362