Murine gammaherpesvirus-induced fibrosis is associated with the development of alternatively activated macrophages
| Autor: | Judith E. Allen, Bahram Ebrahimi, Marieke A. Hoeve, Babunilayam Gangadharan, Bernadette M. Dutia, Anthony Nash, Susan Rhind |
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| Rok vydání: | 2008 |
| Předmět: |
Receptors
CCR4 Transcription Genetic Immunology Spleen Biology Virus Pathogenesis Mice Immune system Gammaherpesvirinae Th2 Cells Fibrosis Cell Movement medicine Immunology and Allergy Animals ARG1 Receptors Interferon Macrophages Germinal center Cell Biology Macrophage Activation medicine.disease Up-Regulation Kinetics medicine.anatomical_structure Lymphatic system Germ Cells Cytokines |
| Zdroj: | Journal of leukocyte biology. 84(1) |
| ISSN: | 0741-5400 |
| Popis: | Murine gammaherpesvirus 68 (MHV-68) is a natural pathogen of rodents closely related to the human gammaherpesviruses 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-gammaR signaling (IFN-gammaR-/-) 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-gammaR-/- mice, different subsets of splenic macrophages (Mvarphis) are morphologically activated and enter latently infected germinal centers (GCs). Mvarphis coexpressing arginase I (ARG1), a marker of alternative activation of Mvarphis, and murine Mvarphi markers F4/80, ER-TR9, and MOMA-1 are found in GCs of IFN-gammaR-/- 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-gammaR-/- mice. In contrast, inducible NO synthase, associated with classical Mvarphi activation, is up-regulated following infection of wild-type mice but not IFN-gammaR(-/-) mice. Concomitant with the aaMvarphis, transcription of the Th2 cytokines IL-13, IL-21, and IL-5 is up-regulated. Thus, in the absence of IFN-gammaR 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. |
| Databáze: | OpenAIRE |
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