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Open Access Research

TLR9-induced interferon β is associated with protection from gammaherpesvirus-induced exacerbation of lung fibrosis

Tracy R Luckhardt1*, Stephanie M Coomes3, Glenda Trujillo5, Joshua S Stoolman2, Kevin M Vannella2, Urvashi Bhan2, Carol A Wilke2, Thomas A Moore2, Galen B Toews2, Cory Hogaboam4 and Bethany B Moore2

Author Affiliations

1 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, University of Alabama at Birmingham Medical School, Birmingham, AL, USA

2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA

3 Graduate Program in Immunology University of Michigan, Ann Arbor, MI 48109, USA

4 Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA

5 Stony Brook University School of Medicine, Stony Brook, NY, 11794, USA

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Fibrogenesis & Tissue Repair 2011, 4:18  doi:10.1186/1755-1536-4-18

Published: 2 August 2011

Abstract

Background

We have shown previously that murine gammaherpesvirus 68 (γHV68) infection exacerbates established pulmonary fibrosis. Because Toll-like receptor (TLR)-9 may be important in controlling the immune response to γHV68 infection, we examined how TLR-9 signaling effects exacerbation of fibrosis in response to viral infection, using models of bleomycin- and fluorescein isothiocyanate-induced pulmonary fibrosis in wild-type (Balb/c) and TLR-9-/- mice.

Results

We found that in the absence of TLR-9 signaling, there was a significant increase in collagen deposition following viral exacerbation of fibrosis. This was not associated with increased viral load in TLR-9-/- mice or with major alterations in T helper (Th)1 and Th2 cytokines. We examined alveolar epithelial-cell apoptosis in both strains, but this could not explain the altered fibrotic outcomes. As expected, TLR-9-/- mice had a defect in the production of interferon (IFN)-β after viral infection. Balb/c fibroblasts infected with γHV68 in vitro produced more IFN-β than did infected TLR-9-/- fibroblasts. Accordingly, in vitro infection of Balb/c fibroblasts resulted in reduced proliferation rates whereas infection of TLR-9-/- fibroblasts did not. Finally, therapeutic administration of CpG oligodeoxynucleotides ameliorated bleomycin-induced fibrosis in wild-type mice.

Conclusions

These results show a protective role for TLR-9 signaling in murine models of lung fibrosis, and highlight differences in the biology of TLR-9 between mice and humans.