Differential roles of ICAM‐1 and VCAM‐1 in leukocyte‐endothelial cell interactions in skin and brain of MRL/ fas lpr mice

MRL/ fas lpr mice, which undergo a systemic autoimmune disease with similarities to systemic lupus erythematosus (SLE), display reduced pathology and prolonged survival if rendered deficient in ICAM‐1. However, it remains unclear whether this is a result of the ability of ICAM‐1 to promote the immune response or mediate leukocyte recruitment. Therefore, the aim of these studies was to compare the role of ICAM‐1 in the elevated leukocyte‐endothelial interactions, which affect MRL/ fas lpr mice. Intravital microscopy was used to compare leukocyte rolling and adhesion in postcapillary venules in the dermal and cerebral (pial) microcirculations of wild‐type (ICAM +/+ ) and ICAM‐1‐deficient (ICAM‐1 −/− ) MRL/ fas lpr mice. In the dermal microcirculation of 16‐week MRL/ fas lpr mice, leukocyte adhesion was increased relative to nondiseased MRL +/+ mice. However, this increase was abolished in ICAM‐1 −/− MRL/ fas lpr mice. ICAM‐1 deficiency was also associated with reduced dermal pathology. In contrast, in the pial microcirculation, the elevation in leukocyte adhesion observed in ICAM +/+ MRL/ fas lpr mice also occurred in ICAM‐1 −/− MRL/ fas lpr mice. VCAM‐1 expression was detectable in both vascular beds, but higher levels were detected in the pial vasculature. Furthermore, VCAM‐1 blockade significantly reduced leukocyte adhesion and rolling in the cerebral microcirculation of ICAM‐1 −/− MRL/ fas lpr mice. Therefore, ICAM‐1 was critical for leukocyte adhesion in the skin but not the brain, where VCAM‐1 assumed the major function. Given the ongoing development of anti‐adhesion molecule therapies and their potential in inflammatory diseases such as SLE, these data indicate that implementation of these therapies in SLE should take into account the potential for tissue‐specific functions of adhesion molecules.