Regulation of inflammation by collagen-binding integrins alpha 1 beta 1 and alpha 2 beta 1 in models of hypersensitivity and arthritis

Adhesive interactions play an important role in inflammation by promoting l eukocyte attachment and extravasation from the vasculature into the periphe ral tissues. However, the importance of adhesion molecules within the extra cellular 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, alpha 1 beta 1 and alpha 2 be ta 1, in several in vivo models of inflammation. mAb's against murine alpha 1 and alpha 2 were found to significantly inhibit effector phase inflammat ory responses in animal models of delayed-type hypersensitivity (DTH), cont act hypersensitivity (CHS), and arthritis. Mice that were al-deficient also showed decreased inflammatory responses in the CHS and arthritis models wh en compared with wild-type mice. Decreased leukocyte infiltration and edema formation accompanied inhibition of antigen-specific models of inflammatio n, as nonspecific inflammation induced by croton oil was not inhibited. Thi s study demonstrates the importance in vivo of alpha 1 beta 1 and alpha 2 b eta 1, the collagen-binding integrins, in inflammatory diseases. The study also extends the role of integrins in-inflammation beyond leukocyte attachm ent and extravasation at the vascular endothelial interface, revealing the extracellular matrix environment of peripheral tissues as a new point of in tervention for adhesion-based therapies.