The Journal of Experimental Medicine
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Published online September 8, 2008
doi:10.1084/jem.20080421
The Journal of Experimental Medicine, Vol. 205, No. 10, 2319-2337
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Getts et al.
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*West Nile Virus
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ARTICLE

 Ly6c+ "inflammatory monocytes" are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis

Daniel R. Getts1,2, Rachael L. Terry1,2, Meghann Teague Getts1,2, Marcus Müller3, Sabita Rana1,2, Bimmi Shrestha1, Jane Radford1,2, Nico Van Rooijen3,4, Iain L. Campbell2,3, and Nicholas J.C. King1,2

1 The Discipline of Pathology, School of Medical Sciences, 2 Bosch Institute, Faculty of Medicine, and 3 School of Molecular and Microbial Biosciences, Faculty of Science, The University of Sydney, Sydney NSW 2006, Australia
4 Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit Medical Center, Vrije Universiteit, 1007 MB Amsterdam, Netherlands

CORRESPONDENCE Nicholas J.C. King: nickk{at}pathology.usyd.edu.au

In a lethal West Nile virus (WNV) model, central nervous system infection triggered a threefold increase in CD45int/CD11b+/CD11c– microglia at days 6–7 postinfection (p.i.). Few microglia were proliferating, suggesting that the increased numbers were derived from a migratory precursor cell. Depletion of "circulating" (Gr1–(Ly6Clo)CX3CR1+) and "inflammatory" (Gr1hi/Ly6Chi/CCR2+) classical monocytes during infection abrogated the increase in microglia. C57BL/6 chimeras reconstituted with cFMS–enhanced green fluorescent protein (EGFP) bone marrow (BM) showed large numbers of peripherally derived (GFP+) microglia expressing GR1+(Ly6C+) at day 7 p.i., suggesting that the inflammatory monocyte is a microglial precursor. This was confirmed by adoptive transfer of labeled BM (Ly6Chi/CD115+) or circulating inflammatory monocytes that trafficked to the WNV-infected brain and expressed a microglial phenotype. CCL2 is a chemokine that is highly expressed during WNV infection and important in inflammatory monocyte trafficking. Neutralization of CCL2 not only reduced the number of GFP+ microglia in the brain during WNV infection but prolonged the life of infected animals. Therefore, CCL2-dependent inflammatory monocyte migration is critical for increases in microglia during WNV infection and may also play a pathogenic role during WNV encephalitis.

Abbreviations used: ANOVA, analysis of variance; BBB, blood-brain barrier; C-L, clodronate-loaded; CNS, central nervous system; D-L, Dil-labeled; H&E, hematoxylin and eosin; IHC, immunohistochemistry; p.i., postinfection; WNV, West Nile virus.

D.R. Getts' present address is Department of Microbiology and Immunology, Northwestern University, Chicago, IL.

B. Shrestha's present address is Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.

M. Müller's present address is Department of Neurology, University of Bonn, 53105 Bonn, Germany.

© 2008 Getts et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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