Collagen XIII induced in vascular endothelium mediates alpha1beta1 integrin-dependent transmigration of monocytes in renal fibrosis.
Alport syndrome is a common hereditary basement membrane disorder caused by mutations in the collagen IV α3, α4, or α5 genes that results in progressive glomerular and interstitial renal disease. Interstitial monocytes that accumulate in the renal cortex from Alport mice are immunopositive for integrin α1β1, while only a small fraction of circulating monocytes are immunopositive for this integrin. We surmised that such a disparity might be due to the selective recruitment of α1β1-positive monocytes. In this study, we report the identification of collagen XIII as a ligand that facilitates this selective recruitment of α1β1 integrin-positive monocytes. Collagen XIII is absent in the vascular endothelium from normal renal cortex and abundant in Alport renal cortex. Neutralizing antibodies against the binding site in collagen XIII for α1β1 integrin selectively block VLA1-positive monocyte migration in transwell assays. Injection of these antibodies into Alport mice slows monocyte recruitment and protects against renal fibrosis. Thus, the induction of collagen XIII in endothelial cells of Alport kidneys mediates the selective recruitment of α1β1 integrin-positive monocytes and may potentially serve as a therapeutic target for inflammatory diseases in which lymphocyte/monocyte recruitment involves the interaction with α1β1 integrin.
Dennis
Jameel
J
Department of Genetics, Boys Town National Research Hospital, and Department of Immunology, Creighton University, 555 North 30 St., Omaha, NE 68131, USA.
Meehan
Daniel T
DT
Delimont
Duane
D
Zallocchi
Marisa
M
Perry
Greg A
GA
O'Brien
Stacie
S
Tu
Hongmin
H
Pihlajaniemi
Taina
T
Cosgrove
Dominic
D
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D016466:CHO Cells; D002478:Cells, Cultured; D024181:Collagen Type XIII / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005355:Fibrosis; D039222:Integrin alpha1beta1 / Q000235:genetics / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000502:physiology*; D009394:Nephritis, Hereditary / Q000473:pathology* / Q000503:physiopathology*; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*
D000906:Antibodies; D024181:Collagen Type XIII; D039222:Integrin alpha1beta1