Published Online
on October 9, 2006

A more recent version of this article appeared on October 24, 2006

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Submitted on November 14, 2005
Revised on June 26, 2006
Accepted on July 21, 2006

Induction of Macrophage Chemotaxis by Aortic Extracts of the mgR Marfan Mouse Model and a GxxPG-Containing Fibrillin-1 Fragment

Gao Guo DMD, Patrick Booms PhD, Marc Halushka MD, PhD, Harry C. Dietz MD, Andreas Ney BSc, Sigmar Stricker PhD, Jochen Hecht MSc, Stefan Mundlos MD, and Peter N. Robinson MD, MSc^*

From the Institute of Medical Genetics, Charité Universitätsmedizin, Humboldt University, Berlin, Germany (G.G., P.B., A.N., S.M., P.N.R.); Department of Pathology (M.H.), Institute of Genetic Medicine, and Howard Hughes Medical Institute, Departments of Pediatrics, Medicine, and Molecular Biology and Genetics (H.C.D.), Johns Hopkins University School of Medicine, Baltimore, Md; and Max Planck Institute for Molecular Genetics, Berlin, Germany (S.S., J.H., S.M.).

^* To whom correspondence should be addressed. E-mail: peter.robinson{at}charite.de.

Background--The primary cause of early death in untreated Marfan syndrome (MFS) patients is aortic dilatation and dissection.

Methods and Results--We investigated whether ascending aortic samples from the fibrillin-1-underexpressing mgR mouse model for MFS or a recombinant fibrillin-1 fragment containing an elastin-binding protein (EBP) recognition sequence can act as chemotactic stimuli for macrophages. Both the aortic extracts from the mgR/mgR mice and the fibrillin-1 fragment significantly increased macrophage chemotaxis compared with extracts from wild-type mice or buffer controls. The chemotactic response was significantly diminished by pretreatment of macrophages with lactose or with the elastin-derived peptide VGVAPG and by pretreatment of samples with a monoclonal antibody directed against an EBP recognition sequence. Mutation of the EBP recognition sequence in the fibrillin-1 fragment also abolished the chemotactic response. These results indicate the involvement of EBP in mediating the effects. Additionally, investigation of macrophages in aortic specimens of MFS patients demonstrated macrophage infiltration in the tunica media.

Conclusions--Our findings demonstrate that aortic extracts from mgR/mgR mice can stimulate macrophage chemotaxis by interaction with EBP and show that a fibrillin-1 fragment possesses chemotactic stimulatory activity similar to that of elastin degradation peptides. They provide a plausible molecular mechanism for the inflammatory infiltrates observed in the mgR mouse model and suggest that inflammation may represent a component of the complex pathogenesis of MFS.

Key words: chemotaxis • elastin-binding proteins • fibrillin • Marfan syndrome

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