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

• Published in: Journal of leukocyte biology Vol. 84; no. 1; pp. 50 - 58
• Main Authors: Gangadharan, Babunilayam, Hoeve, Marieke A., Allen, Judith E., Ebrahimi, Bahram, Rhind, Susan M., Dutia, Bernadette M., Nash, Anthony A.
• Format: Journal Article
• Language: English
• Published: England Society for Leukocyte Biology 01-07-2008
• Subjects: Animals; arginase 1; Cell Movement; Cytokines - genetics; Epstein-Barr virus; fibrogenesis; Fibrosis; Gammaherpesvirinae - physiology; Germ Cells - virology; Human herpesvirus 8; Interferon gamma Receptor; Kinetics; Macrophage Activation - immunology; Macrophages - pathology; Macrophages - virology; Mice; Murine gammaherpesvirus 68; Receptors, CCR4 - metabolism; Receptors, Interferon - deficiency; spleen; Spleen - pathology; Spleen - virology; Th2; Th2 Cells - immunology; Transcription, Genetic; Up-Regulation; virus infection
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.0507270

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