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₄ Integrin-Dependent Leukocyte Recruitment Does Not Require VCAM-1 in a Chronic Model of Inflammation¹

Brent Johnston^*, Alex Chee^*, Thomas B. Issekutz, Tatiana Ugarova, Alison Fox-Robichaud^*, Michael J. Hickey^* and Paul Kubes^2,*

^* Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada; Dalhousie Inflammation Group, Departments of Pediatrics, Medicine, Immunology, and Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; and Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland, OH 44195

Rats immunized with Mycobacterium butyricum in Freund’s adjuvant develop a chronic vasculitis, with large increases in leukocyte rolling and adhesion in mesenteric postcapillary venules that are significantly inhibited with an ₄ integrin Ab. Using intravital microscopy to visualize chronically inflamed microvessels, we demonstrated that ₄ integrin-dependent leukocyte rolling and adhesion was inhibited with a ß₁ integrin, but not a ß₇ integrin Ab. To date, VCAM-1 has been presumed to be the primary ligand for ₄ß₁ integrin in the vasculature. However, ₄ß₁ integrin-dependent interactions were not reduced by monoclonal or polyclonal VCAM-1 Abs or a VCAM-1 antisense oligonucleotide despite increased VCAM-1 expression in the mesenteric vasculature. To ensure that the VCAM-1 Abs were functional and used at saturating concentrations, blood from Ab-treated rats was perfused over monolayers of CHO cells transfected with rat VCAM-1. Sufficient ₄ integrin or VCAM-1 Ab was present to inhibit leukocyte interactions with rat VCAM-1 by 95–100%. Under in vitro flow conditions, only mononuclear leukocytes were recruited from blood of control rats onto purified VCAM-1. However, neutrophils were also recruited onto VCAM-1 from whole blood of adjuvant-immunized animals via ₄ integrin. Another ligand for ₄ß₁ integrin is the connecting segment-1 (CS-1) region of fibronectin. An Ab to the CS-1 portion of fibronectin, which did not reduce rolling and adhesion in adjuvant arthritis animals, completely inhibited leukocyte adhesion to CS-1 under static conditions. These findings provide the first evidence that ₄ß₁ integrin-dependent leukocyte rolling and adhesion can occur in vivo via a mechanism other than VCAM-1.