CD40-CD40 ligand mediates the recruitment of leukocytes and platelets in the inflamed murine colon.
OBJECTIVE
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.
Vowinkel
Thorsten
T
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
Anthoni
Christoph
C
Wood
Katherine C
KC
Stokes
Karen Y
KY
Russell
Janice
J
Gray
Laura
L
Bharwani
Sulaiman
S
Senninger
Norbert
N
Alexander
J Steven
JS
Krieglstein
Christian F
CF
Grisham
Matthew B
MB
Granger
D Neil
DN
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D003092:Colitis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D036904:Leukocyte Rolling; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018715:Microscopy, Video; D009195:Peroxidase / Q000032:analysis; D010973:Platelet Adhesiveness; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014192:Trapidil / Q000494:pharmacology; D014699:Venules / Q000378:metabolism / Q000503:physiopathology
D019013:CD40 Antigens; D010975:Platelet Aggregation Inhibitors; D023201:CD40 Ligand; D016264:Dextran Sulfate; D009195:Peroxidase; D014192:Trapidil