LXR signaling controls homeostatic dendritic cell maturation

Victor Bosteels, Sandra Maréchal, Clint De Nolf, Sofie Rennen, Jonathan Maelfait, Simon J. Tavernier, Jessica Vetters, Evelien Van De Velde, Farzaneh Fayazpour, Kim Deswarte, Alexander Lamoot, Julie Van Duyse, Liesbet Martens, Cédric Bosteels, Ria Roelandt, Annelies Emmaneel, Sofie Van Gassen, Louis Boon, Gert Van Isterdael, Isabelle GuillasNiels Vandamme, Doris Höglinger, Bruno G. De Geest, Wilfried Le Goff, Yvan Saeys, Kodi S. Ravichandran, Bart N. Lambrecht, Sophie Janssens

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Dendritic cells (DCs) mature in an immunogenic or tolerogenic manner depending on the context in which an antigen is perceived, preserving the balance between immunity and tolerance. Whereas the pathways driving immunogenic maturation in response to infectious insults are well-characterized, the signals that drive tolerogenic maturation during homeostasis are still poorly understood. We found that the engulfment of apoptotic cells triggered homeostatic maturation of type 1 conventional DCs (cDC1s) within the spleen. This maturation process could be mimicked by engulfment of empty, nonadjuvanted lipid nanoparticles (LNPs), was marked by intracellular accumulation of cholesterol, and was highly specific to cDC1s. Engulfment of either apoptotic cells or cholesterol-rich LNPs led to the activation of the liver X receptor (LXR) pathway, which promotes the efflux of cellular cholesterol, and repressed genes associated with immunogenic maturation. In contrast, simultaneous engagement of TLR3 to mimic viral infection via administration of poly(I:C)-adjuvanted LNPs repressed the LXR pathway, thus delaying cellular cholesterol efflux and inducing genes that promote T cell–mediated immunity. These data demonstrate that conserved cellular cholesterol efflux pathways are differentially regulated in tolerogenic versus immunogenic cDC1s and suggest that administration of nonadjuvanted cholesterol-rich LNPs may be an approach for inducing tolerogenic DC maturation.

Original languageEnglish
Article numbereadd3955
JournalScience immunology
Volume8
Issue number83
DOIs
StatePublished - May 2023

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