Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity
Open accessAbstract
Autoimmune diseases such as systemic lupus erythematosus (SLE) are associated with increased cardiovascular disease and reduced plasma high-density lipoprotein (HDL) levels. HDL mediates cholesterol efflux from immune cells via the ATP binding cassette transporters A1 and G1 (ABCA1/G1). The significance of impaired cholesterol efflux pathways in autoimmunity is unknown. We observed that Abca1/g1-deficient mice develop enlarged lymph nodes (LNs) and glomerulonephritis suggestive of SLE. This lupus-like phenotype was recapitulated in mice with knockouts of Abca1/g1 in dendritic cells (DCs), but not in macrophages or T cells. DC-Abca1/g1 deficiency increased LN and splenic CD11b+ DCs, which displayed cholesterol accumulation and inflammasome activation, increased cell surface levels of the granulocyte macrophage-colony stimulating factor receptor, and enhanced inflammatory cytokine secretion. Consequently, DC-Abca1/g1 deficiency enhanced T cell activation and T h 1 and T h 17 cell polarization. Nlrp3 inflammasome deficiency diminished the enlarged LNs and enhanced T h 1 cell polarization. These findings identify an essential role of DC cholesterol efflux pathways in maintaining immune tolerance.
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Dendritic cells lacking both ABCA1 and ABCG1 have enhanced inflammasome activation, ultimately resulting in enhanced T cell activation and polarization to the Th1 and Th17 types.
“Dendritic cells lacking both ABCA1 and ABCG1 have enhanced inflammasome activation, ultimately resulting in enhanced T cell activation and polarization to the Th1 and Th17 types (74).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [74]
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“Previous studies have suggested that GMCSF induces the secretion of these cytokines by DCs (Codarri et al., 2011; El-Behi et al., 2011; Sonderegger et al., 2008), linking GM-CSF signaling with autoimmunity.”
BackgroundEl-Behi, M., Ciric, B., Dai, H., Yan, Y., Cullimore, M., Safavi, F., Zhang, G.-X., Dittel, B. N., & Rostami, A. (2011) · Nature Immunology · doi:10.1038/ni.2031 · Cited by 1,071 · cited 4× · see citing works
“Previous studies have suggested that GMCSF induces the secretion of these cytokines by DCs (Codarri et al., 2011; El-Behi et al., 2011; Sonderegger et al., 2008), linking GM-CSF signaling with autoimmunity.”
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“Dendritic cells lacking both ABCA1 and ABCG1 have enhanced inflammasome activation, ultimately resulting in enhanced T cell activation and polarization to the T helper 1 (T H 1) and T H 17 types ( 86 ).”
- Authors
- Westerterp, M., Gautier, E. L., Ganda, A., Molusky, M. M., Wang, W., Fotakis, P., Wang, N., Randolph, G. J., D'Agati, V. D., Yvan-Charvet, L., & Tall, A. R.
- Affiliations
- University Medical Center Groningen (NL)
- Washington University in St. Louis (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Westerterp, Marit
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 25
- Issue
- 6
- Pages
- 1294-1304.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5514787
- OpenAlex
- W2611459561
- Cited by
- 218
- References
- 5
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 25 · 2023: 28 · 2022: 30 · 2021: 32 · 2020: 18 · 2019: 23 · 2018: 17 · 2017: 5 · 2016: 1
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- NIH (HL107653, T32HL007343, S10RR027050)
- Netherlands Organization of Scientific Research (917.15.350)
- UMCG Rosalind Franklin Fellowship
- American Heart Association (SDG2160053)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- dendritic cells, cholesterol accumulation, cholesterol efflux, inflammasome, adaptive immunity, immune tolerance, dendritic cell polarization, lipid metabolism
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 1, Animals, Cholesterol, Dendritic Cells, Immune Tolerance, Mice, Knockout, Th1 Cells, Mice, Adaptive Immunity, Th17 Cells, Inflammasomes, ATP Binding Cassette Transporter 1
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