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Published online before print September 22, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0406295

Received for publication April 30, 2006.
Revised August 29, 2006.
Accepted for publication September 1, 2006.

Article

Depletion of MCP-1 increases development of herpetic stromal keratitis by innate immune modulation

Bumseok Kim ^*, Pranita P. Sarangi ^*, Yunsang Lee ^*, Shilpa Deshpande Kaistha ^*, Sujin Lee , and Barry T. Rouse ^*@

*Department of Microbiology and Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, USA; and Department of Pediatric Infectious Disease, Vanderbilt University, Nashville, Tennessee, USA

^@ To whom correspondence should be addressed. E-mail: btr{at}utk.edu.

	Abstract

Chemokines are important chemoattractant inflammatory molecules, but their interdependent network in disease pathogenesis remains unclear. Studies in mouse models have shown that herpetic stromal keratitis (SK) is produced by the consequence of a tissue-destructive immunoinflammatory reaction involving herpes simplex virus type 1 (HSV) infection. Here we found that ocular HSV infection leads to increased expression of monocyte chemoattractant protein-1 (MCP-1), one of the major chemoattractants for immune cells that express CCR2, in the SK cornea. However, MCP-1 is unlikely to be a chemoattractant for infiltrating Gr-1⁺, CD11b⁺ cells in SK, as these cells are found to be CCR2 negative. Nevertheless, infection of MCP-1^-/- mice resulted in more severe SK lesion severity compared with WT mice (P < 0.01). We demonstrated that the loss of MCP-1 in the SK cornea caused a significant overexpression of macrophage inflammatory protein-2 (MIP-2) (P < 0.01) on days 2 and 4 postinfection and increased infiltration of inflammatory cells (Gr-1-high and CD11b⁺) expressing CXCR2, a receptor for MIP-2, into the cornea. Subsequently, increased infiltration of inflammatory cells accelerated by MIP-2 overexpression might result in the high production of inflammatory molecules, including vascular endothelial growth factor (VEGF) and IL-1 in SK, as well as CpG oligodeoxynucleotide (ODN)-implanted eyes of MCP-1^-/- mice. These results indicate that MCP-1 in the SK cornea might regulate the expression of other chemokines, as well as the infiltration of inflammatory cells and control development of SK.

Key Words: chemokine • Herpes simplex virus • cornea

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