Introduction: Atherosclerosis is an inflammatory disease in which monocyte/macrophages and Th1 cells are crucial cell types. The CXC-chemokine CXCL10 might play a pivotal role in its pathogenesis as it mediates chemoattraction of these cells. We previously found that high CXCL10 levels in human carotid plaques are associated with a vulnerable phenotype. Moreover, we identified CXCL10 as a possible biomarker for vulnerability in a mouse model for vulnerable plaque. The aim of the current study was to evaluate if CXCL10 has a critical role in the development of plaque vulnerability.
Methods: Atherosclerosis-susceptible female ApoE -/-mice on high fat, high cholesterol diet were instrumented with a perivascular shear stress-altering plastic cylinder to induce vulnerable plaque. In the first three weeks following surgery, mice were injected 3 times/week with a bioactivity-neutralizing CXCL10 antibody. After 9 weeks, plaques were harvested and sections were evaluated for macrophages (CD68), immune activation (MHC class II), smooth muscle cells (a-actin), lipids (Oil Red O) and collagen (picrosirius red).
Results: Lesion sizes were equal in both the intervention group and the control group. Also lipid accumulation was comparable in both groups. Despite unaffected macrophage content (30.1 vs 28.7% p = 0.73), we did find a 2-fold reduction of MHC class-II expression (4.9 vs 14.5% p = 0.011) in the antibody-treated group. This decline in activation of the immune system coincided with an increase in the presence of smooth muscle cells (12.6 vs 4.2% p = 0.034) and an increase in collagen content (9.7 vs 21.8% p = 0.014).
Conclusion: This study confirms a pivotal role of CXCL10 in the development of vulnerable plaque. Inhibiting CXCL10 resulted in an increase of plaque stability by decreasing immune activation and increasing smooth muscle cell and collagen content. Accordingly, CXCL10 is a potential marker for both diagnostic and therapeutic intervention.
ANTI-HLA CLASS I ANTIBODY SIGNAL TRANSDUCTION IN ENDOTHELIAL CELLS AND SMOOTH MUSCLE CELLS.