Xcr1⁺ type 1 conventional dendritic cells are essential mediators for atherosclerosis progression

Area of Science:

• Immunology
• Cardiovascular Research
• Cell Biology

Background:

• Atherosclerosis involves lipid accumulation, foam cell formation, and inflammation in aortic lesions.
• The cellular mechanisms driving the inflammatory response in atherosclerotic plaques are not fully understood.
• Xcr1-expressing type 1 conventional dendritic cells (cDC1) are potent antigen-presenting cells, but their role in atherosclerosis is debated.

Purpose of the Study:

• To investigate the role of cDC1 cells in the development and progression of atherosclerosis.
• To explore the potential of targeting cDC1 cells via the Xcl1-Xcr1 axis for immunotherapies.

Main Methods:

• Confirmed presence of cDC1 in human atherosclerotic plaques and correlated numbers with disease progression in mice.
• Generated and utilized a novel genetic model (Xcr1Cre-Gfp Rosa26LSL-DTA Apoe-/-) to constitutively deplete cDC1 in vivo.
• Employed single-cell RNA sequencing to analyze cDC1 heterogeneity under hyperlipidemic conditions.
• Created Xcl1-/- Apoe-/- mice to investigate the Xcl1-Xcr1 pathway's involvement.

Main Results:

• Increased cDC1 numbers were associated with atherosclerosis progression in mice.
• Constitutive cDC1 depletion significantly reduced atherosclerotic lesion size and suppressed CD4+/CD8+ T cell activation.
• Macrophage populations and serum lipid levels remained unchanged in cDC1-depleted mice.
• Xcl1 deficiency led to decreased atherosclerotic plaque formation and reduced aortic cDC1 accumulation.

Conclusions:

• cDC1 cells play a critical, pro-atherogenic role in disease progression.
• The Xcl1-Xcr1 axis is important for cDC1 accumulation and function in atherosclerosis.
• Targeting cDC1 cells, potentially via Xcl1, represents a promising immunotherapeutic strategy for atherosclerosis.