Discoidin domain receptor 1 on bone marrow-derived cells promotes macrophage accumulation during atherogenesis.
BACKGROUND
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.
Franco
Christopher
C
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Britto
Karen
K
Wong
Eric
E
Hou
Guangpei
G
Zhu
Su-Ning
SN
Chen
Mian
M
Cybulsky
Myron I
MI
Bendeck
Michelle P
MP
D000818:Animals; D000963:Antimetabolites; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001854:Bone Marrow Cells / Q000473:pathology*; D016026:Bone Marrow Transplantation; D001973:Bromodeoxyuridine; D024141:Collagen Type IV / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D011975:Receptors, Mitogen / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D051876:Sex-Determining Region Y Protein / Q000235:genetics; D018183:Transplantation Chimera; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000963:Antimetabolites; D024141:Collagen Type IV; D008055:Lipids; D011973:Receptors, LDL; D011975:Receptors, Mitogen; D051876:Sex-Determining Region Y Protein; C497746:Sry protein, mouse; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D001973:Bromodeoxyuridine