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

Lama Almulki^*,, Kousuke Noda^*,, Reza Amini^*,, Alexander Schering^*,, Rebecca C. Garland^*,, Shintaro Nakao^*,, Toru Nakazawa^*,, Toshio Hisatomi^*,, Kennard L. Thomas^*,, Sharmila Masli^*, and Ali Hafezi-Moghadam^*,,1

^* Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA;

Angiogenesis Laboratory, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts, USA; and

Schepens Eye Research Institute, Boston, Massachusetts, USA

¹Correspondence: Angiogenesis Laboratory, 325 Cambridge Street, 3rd Floor, Boston, MA 02114, USA. E-mail: ali_hafezi-moghadam{at}meei.harvard.edu

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, L., Noda, K., Amini, R., Schering, A., Garland, R. C., Nakao, S., Nakazawa, T., Hisatomi, T., Thomas, K. L., Masli, S., Hafezi-Moghadam, A. Surprising up-regulation of P-selectin glycoprotein ligand-1 (PSGL-1) in endotoxin-induced uveitis.

Key Words: leukocyte rolling velocity • autoperfused micro-flow chamber • lipopolysaccharides • adhesion molecules • acute immune response