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Critical Role of the ₄ Integrin/VCAM-1 Pathway in Cerebral Leukocyte Trafficking in Lupus-Prone MRL/fas^lpr Mice¹

Will G. James^*, Daniel C. Bullard and Michael J. Hickey^2,*

^* Centre for Inflammatory Diseases, Monash University, Victoria, Australia; and Department of Genomics and Pathobiology, University of Alabama, Birmingham, AL 35294

MRL/fas^lpr mice are affected by a systemic autoimmune disease that results in leukocyte recruitment to a wide range of vascular beds, including the cerebral microvasculature. The mechanisms responsible for the leukocyte trafficking to the brain in these animals are not known. Therefore, the aim of this study was to directly examine the cerebral microvasculature in MRL/fas^lpr mice and determine the molecular mechanisms responsible for this leukocyte recruitment. Intravital microscopy was used to assess leukocyte-endothelial cell interactions (rolling, adhesion) in the pial microcirculation of MRL^+/+ (control) and MRL/fas^lpr mice at 8, 12, and 16 wk of age. Leukocyte rolling and adhesion were rarely observed in MRL^+/+ mice of any age. MRL/fas^lpr mice displayed similar results at 8 and 12 wk. However, at 16 wk, significant increases in leukocyte rolling and adhesion were observed in these mice. Histological analysis revealed that the interacting cells were exclusively mononuclear. Leukocyte rolling was reduced, but not eliminated in P-selectin^-/--MRL/fas^lpr mice. However, leukocyte adhesion was not reduced in these mice, indicating that P-selectin-dependent rolling was not required for leukocyte recruitment to the cerebral vasculature in this model of systemic inflammation. E-selectin blockade also had no effect on leukocyte rolling. In contrast, blockade of either the ₄ integrin or VCAM-1 eliminated P-selectin-independent leukocyte rolling. ₄ Integrin blockade also significantly inhibited leukocyte adhesion. These studies demonstrate that the systemic inflammatory response that affects MRL/fas^lpr mice results in leukocyte rolling and adhesion in the cerebral microcirculation, and that the ₄ integrin/VCAM-1 pathway plays a central role in mediating these interactions.

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