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

Abstract

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.

• Authors: Babunilayam Gangadharan, Marieke A Hoeve, Judith E Allen, Bahram Ebrahimi, Susan M Rhind, Bernadette M Dutia, Anthony A Nash
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 84 Issue 1 Pg. 50-8 (Jul 2008) ISSN: 0741-5400 [Print] United States
• PMID: 18436582 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Receptors, CCR4
• Receptors, Interferon
• interferon gamma receptor

Topics

• Animals
• Cell Movement
• Cytokines (genetics)
• Fibrosis
• Gammaherpesvirinae (physiology)
• Germ Cells (virology)
• Kinetics
• Macrophage Activation (immunology)
• Macrophages (pathology, virology)
• Mice
• Receptors, CCR4 (metabolism)
• Receptors, Interferon (deficiency)
• Spleen (pathology, virology)
• Th2 Cells (immunology)
• Transcription, Genetic
• Up-Regulation