Regulation of inflammation by collagen-binding integrins alpha1beta1 and alpha2beta1 in models of hypersensitivity and arthritis.
Adhesive interactions play an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. However, the importance of adhesion molecules within the extracellular matrix-rich environment of peripheral tissues, in which cells must migrate and be activated, has not been well explored. We investigated the role of the major collagen-binding integrins, alpha1beta1 and alpha2beta1, in several in vivo models of inflammation. mAb's against murine alpha1 and alpha2 were found to significantly inhibit effector phase inflammatory responses in animal models of delayed-type hypersensitivity (DTH), contact hypersensitivity (CHS), and arthritis. Mice that were alpha1-deficient also showed decreased inflammatory responses in the CHS and arthritis models when compared with wild-type mice. Decreased leukocyte infiltration and edema formation accompanied inhibition of antigen-specific models of inflammation, as nonspecific inflammation induced by croton oil was not inhibited. This study demonstrates the importance in vivo of alpha1beta1 and alpha2beta1, the collagen-binding integrins, in inflammatory diseases. The study also extends the role of integrins in inflammation beyond leukocyte attachment and extravasation at the vascular endothelial interface, revealing the extracellular matrix environment of peripheral tissues as a new point of intervention for adhesion-based therapies.
de Fougerolles
A R
AR
Biogen Inc., Cambridge, Massachusetts 02142, USA. Tony_de_Fougerolles@Biogen.com
Sprague
A G
AG
Nickerson-Nutter
C L
CL
Chi-Rosso
G
G
Rennert
P D
PD
Gardner
H
H
Gotwals
P J
PJ
Lobb
R R
RR
Koteliansky
V E
VE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D001168:Arthritis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000502:physiology*; D003094:Collagen / Q000378:metabolism* / Q000633:toxicity; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D017453:Dermatitis, Irritant / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D004487:Edema / Q000209:etiology / Q000517:prevention & control; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D039222:Integrin alpha1beta1; D016023:Integrins / Q000276:immunology / Q000502:physiology*; D007962:Leukocytes / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D038981:Receptors, Collagen
D000911:Antibodies, Monoclonal; D039222:Integrin alpha1beta1; D016023:Integrins; D008070:Lipopolysaccharides; D038981:Receptors, Collagen; D003094:Collagen