LXR signaling controls homeostatic dendritic cell maturation

Area of Science:

• Immunology
• Cell Biology
• Molecular Medicine

Background:

• Dendritic cells (DCs) balance immunity and tolerance through context-dependent maturation.
• Pathways for immunogenic DC maturation are known, but tolerogenic maturation signals remain unclear.

Purpose of the Study:

• Investigate signals driving homeostatic, tolerogenic maturation of type 1 conventional dendritic cells (cDC1s).
• Explore the role of cellular cholesterol in DC maturation.
• Evaluate lipid nanoparticles (LNPs) as a tool for inducing tolerogenic DC maturation.

Main Methods:

• Studied cDC1 maturation in spleen following engulfment of apoptotic cells or engineered LNPs.
• Analyzed intracellular cholesterol accumulation and LXR pathway activation.
• Assessed gene expression related to immunogenic and tolerogenic maturation.
• Utilized poly(I:C)-adjuvanted LNPs to mimic viral infection.

Main Results:

• Engulfment of apoptotic cells or nonadjuvanted LNPs induced cDC1 maturation, marked by cholesterol accumulation and LXR pathway activation.
• LXR pathway activation promoted cholesterol efflux and repressed immunogenic maturation genes.
• Poly(I:C)-adjuvanted LNPs repressed LXR, delayed cholesterol efflux, and induced immunogenic maturation genes.
• Cholesterol efflux pathways are differentially regulated in tolerogenic vs. immunogenic cDC1s.

Conclusions:

• Homeostatic cDC1 maturation is triggered by apoptotic cell engulfment and cholesterol accumulation.
• Nonadjuvanted, cholesterol-rich LNPs can induce tolerogenic DC maturation via LXR pathway activation.
• Targeting cellular cholesterol efflux offers a novel strategy for modulating DC function and immune responses.