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Deficiency of P-Selectin or P-Selectin Glycoprotein Ligand-1 Leads to Accelerated Development of Glomerulonephritis and Increased Expression of CC Chemokine Ligand 2 in Lupus-Prone Mice¹

Xiaodong He^*, Trenton R. Schoeb^*, Angela Panoskaltsis-Mortari, Kurt R. Zinn, Robert A. Kesterson^*, Junxuan Zhang^*, Sharon Samuel^*, M. John Hicks, Michael J. Hickey^¶ and Daniel C. Bullard^2,*

^* Department of Genetics and Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455; Department of Pathology, Baylor College of Medicine, Houston, TX 77030; and ^¶ Department of Medicine, Monash University, Monash Medical Centre, Clayton, Victoria, Australia

The selectins and their ligands mediate leukocyte rolling on endothelial cells, the initial step in the emigration cascade leading to leukocyte infiltration of tissue. These adhesion molecules have been shown to be key promoters of acute leukocyte emigration events; however, their roles in the development of long-term inflammatory responses, including those that occur during chronic inflammatory diseases such as systemic lupus erythematosus, are unclear. To assess participation of P-selectin in such disorders, we studied the progression of systemic lupus erythematosus-like disease in P-selectin-deficient and control MRL/MpJ-Fas^lpr (Fas^lpr) mice. Surprisingly, we found that P-selectin deficiency resulted in significantly earlier mortality, characterized by a more rapid development of glomerulonephritis and dermatitis. Expression of CCL2 (MCP-1) was increased in the kidneys of P-selectin mutant mice and in supernatants of LPS-stimulated primary renal endothelial cell cultures from these mice. A closely similar phenotype, including elevated renal expression of CCL2, was also observed in Fas^lpr mice deficient in the major P-selectin ligand, P-selectin glycoprotein ligand-1. These results indicate that P-selectin and P-selectin glycoprotein ligand-1 are not required for leukocyte infiltration and the development of autoimmune disease in Fas^lpr mice, but rather expression of these adhesion molecules is important for modulating the progression of glomerulonephritis, possibly through down-regulation of endothelial CCL2 expression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grant R01 RR017009 (to D.C.B.).

² Address correspondence and reprint requests to Dr. Daniel C. Bullard, Department of Genetics, University of Alabama at Birmingham, 640A Kaul Building, 720 South 20th Street, Birmingham, AL 35294. E-mail address: dcbullard{at}uab.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; IC, immune complex; PSGL-1, P-selectin glycoprotein ligand-1; MAG₃, mercaptoacetyltriglycine; %ID, percentage of injected dose; DiI,1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate; DiI-Ac-LDL, DiI-conjugated acetylated low-density lipoprotein; vWF, Von Willebrand factor.

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