Background:
Atherosclerosis is a chronic inflammatory disease characterized by plaque formation driven by complex interactions between immune cells, vascular smooth muscle cells, and signaling molecules. Previous studies have demonstrated that the chemokine CCL11, well known for its role in allergic diseases and eosinophil recruitment, is also expressed in atherosclerotic lesions, suggesting a broader role in vascular inflammation. Emerging evidence indicates that CCL11 promotes leukocyte recruitment as well as smooth muscle cell migration and contributes to oxidative stress. However, its precise contribution to plaque progression and stability remains incompletely understood.
This project investigates the specific role of CCL11 in atherosclerotic lesion development, immune cell infiltration, and vascular remodeling.
Methods:
Male Apoe-/-Ccl11-/- and Apoe-/-Ccl11+/+ mice were fed a high-fat Western diet for 16 weeks. Circulating immune cell populations were analyzed by flow cytometry, and plasma cholesterol levels were measured. For local vascular effects, brachiocephalic arteries were examined histologically, including quantification of lesion size, assessment of plaque composition, and fibrous cap cellularity (defined as the luminal 30 µm of the plaque). In addition, in vitro experiments with peritoneal macrophages and smooth muscle cells were performed to further investigate the mechanistic role of CCL11.
Results:
Ccl11 deficiency in male Apoe-/- mice significantly reduced circulating leukocyte counts (281 vs. 771 cells per µl blood; p = 0.016), including neutrophils (146 vs. 369; p = 0.006), eosinophils (28 vs.127; p = 0.005), basophils (6 vs. 15; p = 0.039), and monocytes (27 vs. 100; p = 0.004) compared with Apoe-/-Ccl11+/+ controls. In Ccl11-deficient mice, histological analysis of the fibrous cap in brachiocephalic artery lesions revealed significantly reduced macrophage infiltration (23.60% vs. 37.40% of fibrous cap area; p = 0.018) together with increased smooth muscle cell content (11.53% vs. 4.48%; p = 0.036) and higher collagen content (53.81% vs. 36.73%; p = 0.031), pointing to a more stable plaque phenotype. At the whole-plaque level, total lesion size, lipid accumulation, collagen content, and necrotic core area did not differ between the groups, whereas smooth muscle cell content was also significantly increased in Ccl11-deficient mice (7.21% vs. 2.31% of total plaque area; p = 0.018). In vitro, co-stimulation with CCL11 and LPS resulted in significantly increased MMP-9 production by peritoneal macrophages compared with LPS stimulation alone (2.27 ng/ml vs. 0.43 ng/ml; p = 0.001).
Conclusion:
CCL11 modulates circulating leukocytes and fibrous cap composition; its deficiency promotes a more stable phenotype characterized by a smooth muscle cell-rich, collagen-enhanced fibrous cap with reduced inflammatory cell infiltration. These findings indicate a previously unrecognized role of CCL11 in contributing to plaque vulnerability in atherosclerosis.
