CD40–CD40 Ligand Mediates the Recruitment of Leukocytes and Platelets in the Inflamed Murine Colon

Background & Aims: Although the CD40–CD40 ligand (CD40L) signaling pathway has been implicated in the pathogenesis of a variety of diseases, including inflammatory bowel disease, the nature of its contribution to intestinal inflammation remains poorly understood. The aim of this study was to determine whether CD40–CD40L contributes to the intestinal inflammatory response, tissue injury, and disease activity elicited by dextran sodium sulphate (DSS) through the modulation of leukocyte and platelet recruitment in the colonic microvasculature. Methods: Wild-type (WT), CD40^−/−, and CD40L^−/− mice were fed DSS drinking water. On day 6, intravital videomicroscopy was performed to monitor leukocyte and platelet recruitment in colonic venules, with measurements obtained for tissue myeloperoxidase and histology. CD40 expression on colonic endothelium was measured using the dual-radiolabeled antibody technique. Results: A comparison of the responses to DSS-induced colitis in CD40^−/− and CD40L^−/− mice to WT mice revealed a significant attenuation of disease activity and histologic damage, as well as profound reductions in the recruitment of adherent leukocytes and platelets in the mutant mice. Similar down-regulation of the blood cell recruitment responses to DSS was noted in WT mice treated with the CD40–CD40L pathway inhibitor Trapidil. CD40 expression in the colonic vasculature was greatly elevated during DSS-induced inflammation in WT mice, but not in CD40^−/− mice. Conclusions: These findings implicate CD40–CD40L in the pathogenesis of DSS-induced intestinal inflammation, and suggest that modulation of leukocyte and platelet recruitment by activated, CD40-positive endothelial cells in colonic venules may represent a major action of this signaling pathway.

Abbreviations used in this paper: CD40^−/−, CD40 knockout, CD40L, CD40 ligand, CD40L^−/−, CD40L knockout, DAI, disease activity index, DSS, dextran sodium sulphate, HIMEC, human intestinal microvascular endothelial cells, IBD, inflammatory bowel disease, ICAM-1, intercellular adhesion molecule-1, mAb, monoclonal antibody, MPO, myeloperoxidase, VCAM-1, vascular cell adhesion molecule-1, WT, wild type