Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment.
BACKGROUND
The primary cause of early death in untreated Marfan syndrome (MFS) patients is aortic dilatation and dissection.


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.
Guo
Gao
G
Institute of Medical Genetics, Charité Universitätsmedizin, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
Booms
Patrick
P
Halushka
Marc
M
Dietz
Harry C
HC
Ney
Andreas
A
Stricker
Sigmar
S
Hecht
Jochen
J
Mundlos
Stefan
S
Robinson
Peter N
PN
D000818:Animals; D001011:Aorta / Q000737:chemistry*; D002417:Cattle; D002630:Chemotactic Factors / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects*; D004195:Disease Models, Animal; D004549:Elastin / Q000737:chemistry / Q000378:metabolism; D000071838:Fibrillin-1; D000071837:Fibrillins; D008264:Macrophages / Q000187:drug effects*; D008382:Marfan Syndrome / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014020:Tissue Extracts / Q000494:pharmacology; D054392:Adipokines
D002630:Chemotactic Factors; D004549:Elastin; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014020:Tissue Extracts; C000605724:Fbn1 protein, mouse; D054392:Adipokines