Differential roles of ICAM-1 and VCAM-1 in leukocyte-endothelial cell interactions in skin and brain of MRL/faslprmice

Abstract

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.