Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

Marit Westerterp, Emmanuel L. Gautier, Anjali Ganda, Matthew M. Molusky, Wei Wang, Panagiotis Fotakis, Nan Wang, Gwendalyn J. Randolph, Vivette D. D'Agati, Laurent Yvan-Charvet, Alan R. Tall

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

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 Th1 and Th17 cell polarization. Nlrp3 inflammasome deficiency diminished the enlarged LNs and enhanced Th1 cell polarization. These findings identify an essential role of DC cholesterol efflux pathways in maintaining immune tolerance.

Original languageEnglish
Pages (from-to)1294-1304.e6
JournalCell metabolism
Volume25
Issue number6
DOIs
StatePublished - Jun 6 2017

Keywords

  • Abc transporters
  • Nlrp3
  • autoimmunity
  • cholesterol efflux pathways
  • cholesterol transport
  • dendritic cells
  • high-density lipoprotein
  • inflammasome
  • lupus glomerulonephritis

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