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Following intranasal infection, the virus replicates in the lung epithelium prior to establishing latent infection in lymphoid tissue. Infection of mice deficient in IFN-\u03b3R signaling (IFN-\u03b3R\u2212\/\u2212) 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-\u03b3R\u2212\/\u2212 mice, different subsets of splenic macrophages (M\u03d5s) are morphologically activated and enter latently infected germinal centers (GCs). M\u03d5s coexpressing arginase I (ARG1), a marker of alternative activation of M\u03d5s, and murine M\u03d5 markers F4\/80, ER-TR9, and MOMA-1 are found in GCs of IFN-\u03b3R\u2212\/\u2212 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-\u03b1, tissue inhibitor of metalloproteinase-1, matrix metalloproteinase-12, fibronectin, and factor XIIIA in IFN-\u03b3R\u2212\/\u2212 mice. In contrast, inducible NO synthase, associated with classical M\u03d5 activation, is up-regulated following infection of wild-type mice but not IFN-\u03b3R\u2212\/\u2212 mice. Concomitant with the aaM\u03d5s, transcription of the Th2 cytokines IL-13, IL-21, and IL-5 is up-regulated. Thus, in the absence of IFN-\u03b3R 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.<\/jats:p>","DOI":"10.1189\/jlb.0507270","type":"journal-article","created":{"date-parts":[[2008,4,25]],"date-time":"2008-04-25T00:53:56Z","timestamp":1209084836000},"page":"50-58","source":"Crossref","is-referenced-by-count":43,"title":["Murine gammaherpesvirus-induced fibrosis is associated with the development of alternatively activated macrophages"],"prefix":"10.1093","volume":"84","author":[{"given":"Babunilayam","family":"Gangadharan","sequence":"first","affiliation":[{"name":"Centre for Infectious Diseases, University of Edinburgh , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke A","family":"Hoeve","sequence":"additional","affiliation":[{"name":"The Institute of Immunology and Infection Research, University of Edinburgh , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith E","family":"Allen","sequence":"additional","affiliation":[{"name":"The Institute of Immunology and Infection Research, University of Edinburgh , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahram","family":"Ebrahimi","sequence":"additional","affiliation":[{"name":"Division of Medical Microbiology, School of Infection and Host Defence, University of Liverpool , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M","family":"Rhind","sequence":"additional","affiliation":[{"name":"Division of Veterinary Clinical Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette M","family":"Dutia","sequence":"additional","affiliation":[{"name":"Centre for Infectious Diseases, University of Edinburgh , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony A","family":"Nash","sequence":"additional","affiliation":[{"name":"Centre for Infectious Diseases, University of Edinburgh , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,4,24]]},"reference":[{"key":"2023032712472887400_","first-page":"468","article-title":"Isolation of five strains of herpesviruses from two species of free living small rodents","volume":"24","author":"Blaskovic","year":"1980","journal-title":"Acta Virol."},{"key":"2023032712472887400_","doi-asserted-by":"crossref","first-page":"5894","DOI":"10.1128\/jvi.71.8.5894-5904.1997","article-title":"Complete sequence and genomic analysis of murine \u03b3herpesviruses 68","volume":"71","author":"Virgin","year":"1997","journal-title":"J. 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