Critical role of endothelial P-selectin glycoprotein ligand 1 in chronic murine ileitis.
L-selectin ligands might be relevant for inflammatory cell trafficking into the small intestine in a spontaneous model of chronic ileitis (i.e., SAMP1/YitFc mice). Immunoblockade of peripheral node addressin or mucosal addressin cell adhesion molecule 1 failed to ameliorate ileitis, whereas P-selectin glycoprotein ligand 1 (PSGL-1) neutralization attenuated both the adoptively transferred and spontaneous disease. PSGL-1 was detected in venules of mesenteric lymph node and small intestine by immunohistochemistry and confirmed by real-time reverse transcription polymerase chain reaction and flow cytometry. In addition, reconstitution of wild-type mice with PSGL-1(-/-) bone marrow demonstrated that PSGL-1 messenger RNA and PSGL-1 protein expression remained on endothelium, localized within mesenteric lymph node and small intestine. Endothelial PSGL-1 bound P-selectin-IgG and its blockade or genetic deletion altered the recruitment of lymphocytes to the small intestine, as revealed by intravital microscopy and homing studies. Endothelial expression of PSGL-1 adds a new dimension to the various cellular interactions involved in small intestinal recruitment. Thus, the multiple roles of PSGL-1 may explain why targeting this single adhesion molecule results in attenuation of chronic murine ileitis, a disease previously resistant to antiadhesion molecule strategies.
Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. jr3u@virginia.edu
Jesús
J
Rivera-Nieves
Tracy L
TL
Burcin
Timothy S
TS
Olson
Margaret A
MA
Morris
Marcia
M
McDuffie
Fabio
F
Cominelli
Klaus
K
Ley
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D004727:Endothelium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007079:Ileitis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007156:Immunologic Memory; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008643:Mesentery; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein