Murine gammaherpesvirus-induced fibrosis is associated with the development of alternatively activated macrophages.
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.
Gangadharan
Babunilayam
B
Centre for Infectious Diseases, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, UK.
Hoeve
Marieke A
MA
Allen
Judith E
JE
Ebrahimi
Bahram
B
Rhind
Susan M
SM
Dutia
Bernadette M
BM
Nash
Anthony A
AA
D000818:Animals; D002465:Cell Movement; D016207:Cytokines / Q000235:genetics; D005355:Fibrosis; D018142:Gammaherpesvirinae / Q000502:physiology*; D005854:Germ Cells / Q000821:virology; D007700:Kinetics; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000473:pathology / Q000821:virology*; D051379:Mice; D054398:Receptors, CCR4 / Q000378:metabolism; D017471:Receptors, Interferon / Q000172:deficiency; D013154:Spleen / Q000473:pathology / Q000821:virology; D018418:Th2 Cells / Q000276:immunology; D014158:Transcription, Genetic; D015854:Up-Regulation; D000096743:Interferon gamma Receptor
D016207:Cytokines; D054398:Receptors, CCR4; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor