CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation
By Frederick J. Sheedy, A. Grebe, K. Rayner, Parisa Kalantari, Bhama Ramkhelawon, Susan B. Carpenter, Christine E. Becker, H. Ediriweera, A. Mullick, D. Golenbock and 4 more. Nature Immunology, 2013
619 citations recorded by the source corpus.
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.
Subfields: Immunology, Molecular Biology, Surgery
View Paper: https://www.semanticscholar.org/paper/0ef1d7f698a1f4b955e2a19d78c2779310514c52
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Citations in the corpus
- Pathophysiology of Atherosclerosis (2022, background): “Caspase-1 subsequently cleaves the proinflammatory IL-1 family of cytokines into their bioactive forms, IL-1β and IL-18, contributing to inflammation [88].”
- NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. (2018, background): “cholesterol crystallization and can thereby directly activate the NLRP3 inflammasome in macrophages.(27) Of note, CD36 deficiency in Apoe mice resulted in impaired atherosclerotic”
- Inflammation and atherosclerosis: signaling pathways and therapeutic intervention (2022, background): “The PYD domain is also required for ASC selfassociation as well as interaction with NLRP3.”
- NLRP3 inflammasome and its inhibitors: a review (2015, background): “…caused by mitochondrial Ca2+ overload (Iyer et al., 2013; Miao et al., 2014; Zhuang et al., 2015), lysosomal disruption (Hornung et al., 2008; Sheedy et al., 2013; Tseng et al., 2013), autophagic dysfunction (Cho et al., 2014; Shao et al., 2014; Jabir et al., 2015) and the activity of…”
- Monocyte-Macrophages and T Cells in Atherosclerosis (2017, neutral): “Although cholesterol crystals have been implicated in this process (Duewell et al., 2010; Sheedy et al., 2013), other mechanisms are likely to contribute as well (Hoseini et al., 2017).”