Surprising up-regulation of P-selectin glycoprotein ligand-1 (PSGL-1) in endotoxin-induced uveitis.
P-selectin glycoprotein ligand-1 (PSGL-1) is constitutively expressed on leukocytes and was thought to be down-regulated with cell activation. However, this work shows the surprising finding of functional PSGL-1 up-regulation during acute inflammation. PSGL-1 function was studied in our autoperfusion assay, in which blood from a mouse carotid flows through a microchamber coated with a fixed density of P-selectin. Under the inflammatory conditions--uveitis induced by systemic lipopolysaccharide injection--we recorded significantly reduced leukocyte rolling velocity, which suggests PSGL-1 up-regulation; however, flow cytometry showed reduced PSGL-1. When bound leukocytes were released from the vasculature by PSGL-1 blockade, a large peripheral blood leukocyte (PBL) population showed elevated PSGL-1, which could account for the reduced PSGL-1 in the remaining unbound population. In the eye, systemic blockade of PSGL-1 with a monoclonal antibody or recombinant soluble PSGL-1 drastically reduced the severe manifestations of uveitis. Furthermore, PSGL-1 blockade was significantly more effective in reducing retinal leukostasis than was P-selectin blockade. Our results provide surprising evidence for functional PSGL-1 up-regulation in PBLs during acute inflammation. The temporal overlap between PSGL-1 and P-selectin up-regulation reveals an as yet unrecognized collaboration between this receptor-ligand pair, increasing efficiency of the first steps of the leukocyte recruitment cascade.
Almulki
Lama
L
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Noda
Kousuke
K
Amini
Reza
R
Schering
Alexander
A
Garland
Rebecca C
RC
Nakao
Shintaro
S
Nakazawa
Toru
T
Hisatomi
Toshio
T
Thomas
Kennard L
KL
Masli
Sharmila
S
Hafezi-Moghadam
Ali
A
D000818:Animals; D000867:Anterior Chamber / Q000166:cytology; D004731:Endotoxins / Q000633:toxicity*; D007249:Inflammation / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046210:Microfluidic Analytical Techniques; D012160:Retina / Q000166:cytology; D015854:Up-Regulation / Q000502:physiology*; D014605:Uveitis / Q000139:chemically induced* / Q000378:metabolism
D004731:Endotoxins; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein