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Originally published online as doi:10.1189/jlb.0507270 on April 24, 2008

Published online before print April 24, 2008
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(Journal of Leukocyte Biology. 2008;84:50-58.)
© 2008 by Society for Leukocyte Biology

Murine gammaherpesvirus-induced fibrosis is associated with the development of alternatively activated macrophages

Babunilayam Gangadharan*,1,2, Marieke A. Hoeve{dagger},1, Judith E. Allen{dagger}, Bahram Ebrahimi{ddagger}, Susan M. Rhind§, Bernadette M. Dutia* and Anthony A. Nash*,3

* Centre for Infectious Diseases,
§ Division of Veterinary Clinical Sciences, Royal (Dick) School of Veterinary Studies, and
{dagger} The Institute of Immunology and Infection Research, University of Edinburgh, United Kingdom; and
{ddagger} Division of Medical Microbiology, School of Infection and Host Defence, University of Liverpool, United Kingdom

3Correspondence: Centre for Infectious Diseases, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, UK. E-mail: tony.nash{at}ed.ac.uk

ABSTRACT

Murine gammaherpesvirus 68 (MHV-68) is a natural pathogen of rodents closely related to the human {gamma}herpesviruses Kaposi’s sarcoma-associated herpesvirus and EBV. Following intranasal infection, the virus replicates in the lung epithelium prior to establishing latent infection in lymphoid tissue. Infection of mice deficient in IFN-{gamma}R signaling (IFN-{gamma}R–/–) results in a multiple organ fibrosis, in which the spleen is severely affected. We show here that by Day 12 postinfection, prior to development of fibrosis in the spleens of IFN-{gamma}R–/– mice, different subsets of splenic macrophages (M{varphi}s) are morphologically activated and enter latently infected germinal centers (GCs). M{varphi}s coexpressing arginase I (ARG1), a marker of alternative activation of M{varphi}s, and murine M{varphi} markers F4/80, ER-TR9, and MOMA-1 are found in GCs of IFN-{gamma}R–/– mice but not of wild-type mice. Quantitative RT-PCR of spleen RNA confirms induction of ARG1 and in addition, shows up-regulation of found in inflammatory zone 1/resistin-like molecule-{alpha}, tissue inhibitor of metalloproteinase-1, matrix metalloproteinase-12, fibronectin, and factor XIIIA in IFN-{gamma}R–/– mice. In contrast, inducible NO synthase, associated with classical M{varphi} activation, is up-regulated following infection of wild-type mice but not IFN-{gamma}R–/– mice. Concomitant with the aaM{varphi}s, transcription of the Th2 cytokines IL-13, IL-21, and IL-5 is up-regulated. Thus, in the absence of IFN-{gamma}R signaling, MHV-68 initiates a Th2 immune response, leading to alternative activation of macrophages and induction of fibrosis. This system provides an important model for studying the pathogenesis of fibrosis initiated by a latent herpesvirus infection.

Key Words: Th2 • virus infection • arginase 1 • fibrogenesis • spleen






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