Discoidin Domain Receptor 1 on Bone Marrow-derived Cells Promotes Macrophage Accumulation During Atherogenesis

Rationale: We described a critical role for the discoidin domain receptor (DDR)1 collagen receptor tyrosine kinase during atherosclerotic plaque development. Systemic deletion of Ddr1 in Ldlr(-/-) mice accelerated matrix accumulation and reduced plaque size and macrophage content. However, whether these effects reflected an independent role for macrophage DDR1 during atherogenesis remained unresolved.

Methods: In the present study, we performed sex-mismatched bone marrow transplantation using Ddr1(+/+);Ldlr(-/-) and Ddr1(-/-);Ldlr(-/-) mice to investigate the role of macrophage DDR1 during atherogenesis. Chimeric mice with deficiency of DDR1 in bone marrow-derived cells (Ddr1(-/--->+/+)) or control chimeric mice that received Ddr1(+/+);Ldlr(-/-) marrow (Ddr1(+/+-->+/+)) were fed an atherogenic diet for 12 weeks.

Results: We observed a 66% reduction in atherosclerosis in the descending aorta and a 44% reduction in plaque area in the aortic sinus in Ddr1(-/--->+/+) mice compared to Ddr1(+/+-->+/+) mice. Furthermore, we observed a specific reduction in the number of donor-derived macrophages in Ddr1(-/--->+/+) plaques, suggesting that bone marrow deficiency of DDR1 attenuated atherogenesis by limiting macrophage accumulation in the plaque. We have also demonstrated that the effects of DDR1 on macrophage infiltration and accumulation can occur at the earliest stage of atherogenesis, the formation of the fatty streak. Deficiency of DDR1 limited the appearance of 5-bromodeoxyuridine-labeled monocytes/macrophages in the fatty streak and resulted in reduced lesion size in Ldlr(-/-) mice fed a high fat diet for 2 weeks. In vitro studies to investigate the mechanisms involved revealed that macrophages from Ddr1(-/-) mice had decreased adhesion to type IV collagen and decreased chemotactic invasion of type IV collagen in response to monocyte chemoattractant protein-1.

Conclusions: Taken together, our data support an independent and critical role for DDR1 in macrophage accumulation at early and late stages of atherogenesis.