CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation
Open accessAbstract
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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CD36 and TLR4 are key mediators of Aβ-driven microglial activation and inflammasome-associated inflammatory signaling.
“These receptors are well established as key mediators of Aβ-driven microglial activation and inflammasome-associated inflammatory signaling26,27.”
From Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer’s disease models (2026) · cites this paper as [26]
The introductory passage says CD36 cooperates with TLR4–TLR6 to recognize fibrillar Aβ and induce an inflammatory response. The Results section reports Aβ-associated NLRP3 signaling in microglia, but this paper’s experiments establishing CD36-dependent Aβ-induced inflammasome activation used macrophages; its TLR4–TLR6 inflammasome-priming result concerns oxidized LDL, not Aβ. It therefore does not establish both receptors as mediators of Aβ-driven inflammasome signaling in microglia. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAβ oligomers activate microglial pattern-recognition receptors including CD36 and TLR4/6, leading to inflammasome activation and amplification of pro-inflammatory cytokine release.
“Aβ oligomers activate microglial pattern-recognition receptors, including CD36 and TLR4/6, leading to inflammasome activation and amplification of pro-inflammatory cytokine release26,27.”
From Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer’s disease models (2026) · cites this paper as [26]
In ‘CD36 regulates amyloid formation and NLRP3 activation’ (page unavailable), the paper reports that CD36-mediated uptake of soluble Aβ activates NLRP3 and increases IL-1β release in LPS-primed macrophages. It also states that CD36 cooperates with TLR4–TLR6 in recognizing fibrillar Aβ and reports prior evidence of inflammasome activation in microglia. It does not establish the full claimed pathway—Aβ oligomers activating CD36 and TLR4/6 to amplify cytokine release—in microglia. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCholesterol crystals can also form intracellularly after uptake of modified LDL, particularly oxLDL.
“cholesterol crystals can also be formed intracellularly after uptake of modified LDL, particularly oxLDL59.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [59]
OxLDL primes and activates the NLRP3 inflammasome in macrophages in mouse models of atherosclerosis: it primes via the CD36-TLR4-TLR6 complex and, after lysosomal transport, activates via cholesterol crystallization and lysosomal damage.
“OxLDL has been shown both to prime and to activate the NLRP3 inflammasome in macrophages in mouse models of atherosclerosis: first, oxLDL primes the NLRP3 inflammasome by binding to the CD36–TLR4–TLR6 signalling complex on the macrophage surface and, then, after having been transported to lysosomes, the oxLDL activates the NLRP3 inflammasome via induction of cholesterol crystallization and ensuing”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [59]
An alternative pathway has been described for intracellular signaling produced by the binding of Aβ to microglial cells, activating NLRP3 inflammasome.
“Recently, an alternative pathway has been described for intracellular signaling produced by the binding of Aβ to microglial cells, activating NLRP3 inflammasome (Heneka et al., 2013; Sheedy et al., 2013).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Sheedy et al., 2013
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- Authors
- Sheedy, F. J., Grebe, A., Rayner, K. J., Kalantari, P., Ramkhelawon, B., Carpenter, S. B., Becker, C. E., Ediriweera, H. N., Mullick, A. E., Golenbock, D. T., Stuart, L. M., Latz, E., Fitzgerald, K. A., & Moore, K. J.
- Affiliations
- NYU Langone Health (US)
- University of Bonn (DE)
- University of Massachusetts Chan Medical School (US)
- Harvard University (US)
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Moore, Kathryn J
- ORCID
- Venue
- Nature Immunology
- Published
- 2013-06-30
- Volume
- 14
- Issue
- 8
- Pages
- 812-820
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3720827
- OpenAlex
- W2082400315
- Cited by
- 935
- References
- 56
- Citations by year
- 2026: 69 · 2025: 62 · 2024: 66 · 2023: 68 · 2022: 61 · 2021: 104 · 2020: 95 · 2019: 80 · 2018: 76 · 2017: 70 · 2016: 62 · 2015: 55 · 2014: 51 · 2013: 15
- FWCI
- 27.30
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- National Institute on Aging (R01AG032349)
- National Heart, Lung, and Blood Institute (R01HL117334, R01HL093262, R01HL112661)
- National Institute of Allergy and Infectious Diseases (R01AI079198, AI083713, U24AI082660, R01AI083713)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- CD36, NLRP3 inflammasome, sterile inflammation, cholesterol crystals, amyloid fibrils, amylin, oxidized LDL, amyloid-beta, IL-1β, macrophages, endocytosis, lysosomal disruption, atherosclerosis, Alzheimer's disease, diabetes mellitus, pattern recognition receptors
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Alzheimer Disease, Animals, Carrier Proteins, Diabetes Mellitus, Type 2, Inflammation, Lipoproteins, LDL, Mice, Inbred C57BL, Microscopy, Fluorescence, RNA, Mice, Knockout, Microscopy, Confocal, CD36 Antigens, Atherosclerosis, Mice, Interleukin-1beta, Inflammasomes, Real-Time Polymerase Chain Reaction
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