ICAM-1 DIRECTS MIGRATION AND LOCALIZATION OF INTERSTITIAL LEUKOCYTES IN EXPERIMENTAL GLOMERULONEPHRITIS

Recent studies of rat anti-GBM disease have demonstrated a functional role of the ICAM-1/LFA-1 interaction in the entry of leukocytes into the glomerulus and an association between interstitial ICAM-1 expression, leukocyte infiltration and tubulointerstitial damage. In the current study, we used immunogold ultrastructural techniques to identify ICAM-1/LFA-1 interactions in the initiation of interstitial leukocyte infiltration during the first 24 hours of rat accelerated anti-GBM disease. In normal rats, there was weak constitutive ICAM-1 expression in the interstitium: on the endothelial luminal surface of interstitial capillaries, venules and arterioles, on the entire surface of interstitial fibroblast-like cells and confined to the brush border of proximal tubules. As early as 1.5 hours after injection of anti-GBM serum, there was a marked increase in the intensity of ICAM-1 expression, most notably on capillary endothelium, fibroblast-like cells and brush borders of proximal tubules, particularly in the periglomerular/perihilar areas. Mononuclear leukocytes exhibiting strong surface LFA-1 (CD11a and CD18) expression were seen adherent to the endothelium of interstitial capillaries, with ICAM-1 and LFA-1 antigens present at sites of contact. In addition, mononuclear cells migrating into the interstitium showed areas of close apposition to interstitial fibroblast-like cells, and here ICAM-1 and LFA-1 expression were also prominent at the sites of contact. This is the first study to demonstrate sites of ICAM-1/LFA-1 interaction in mononuclear cell migration and localization in glomerulonephritis. The results suggest that up-regulation of periglomerular/peritubular capillary ICAM-1 expression is important for mononuclear cell entry into the interstitium, while interaction with fibroblast-like cells may facilitate movement and subsequent focal accumulation of mononuclear cells at sites within the interstitium.