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Published online before print April 24, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0507270

Received for publication May 2, 2007.
Revised March 12, 2008.
Accepted for publication March 13, 2008.

Article

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

Babunilayam Gangadharan ^*, Marieke A. Hoeve , Judith E. Allen , Bahram Ebrahimi , Susan M. Rhind , Bernadette M. Dutia ^*, and Anthony A. Nash ^*@

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

^@ To whom correspondence should be addressed. E-mail: Tony.Nash{at}ed.ac.uk.

	Abstract

Murine herpesvirus 68 (MHV-68) is a natural pathogen of rodents closely related to the human 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-R signaling (IFN-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-R^-/- mice, different subsets of splenic macrophages (Ms) are morphologically activated and enter latently infected germinal centers (GCs). Ms coexpressing arginase I (ARG1), a marker of alternative activation of Ms (aaMs), and murine M markers F4/80, ER-TR9, and MOMA-1 are found in GCs of IFN-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-, tissue inhibitor of metalloproteinase-1, matrix metalloproteinase-12, fibronectin, and factor XIIIA in IFN-R^-/- mice. In contrast, inducible NO synthase, associated with classical M activation, is up-regulated following infection of wild-type mice but not IFN-R^-/- mice. Concomitant with the aaMs, transcription of the Th2 cytokines IL-13, IL-21, and IL-5 is up-regulated. Thus, in the absence of IFN-R signaling, MHV-68 initiates a Th2 immune response, leading to aaMs 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 • germinal centers • arginase 1