Surprising up-regulation of P-selectin glycoprotein ligand-1 (PSGL-1) in endotoxin-induced uveitis.

Abstract

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.

• Authors: Lama Almulki, Kousuke Noda, Reza Amini, Alexander Schering, Rebecca C Garland, Shintaro Nakao, Toru Nakazawa, Toshio Hisatomi, Kennard L Thomas, Sharmila Masli, Ali Hafezi-Moghadam
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 23 Issue 3 Pg. 929-39 (Mar 2009) ISSN: 1530-6860 [Electronic] United States
• PMID: 19050046 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endotoxins
• Membrane Glycoproteins
• P-selectin ligand protein

Topics

• Animals
• Anterior Chamber (cytology)
• Endotoxins (toxicity)
• Inflammation (metabolism)
• Leukocytes (physiology)
• Male
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Microfluidic Analytical Techniques
• Retina (cytology)
• Up-Regulation (physiology)
• Uveitis (chemically induced, metabolism)