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

Background: We have shown previously that murine gammaherpesvirus 68 (gamma HV68) infection exacerbates established pulmonary fibrosis. Because Toll-like receptor (TLR)-9 may be important in controlling the immune response to gamma HV68 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)-beta after viral infection. Balb/c fibroblasts infected with gamma HV68 in vitro produced more IFN-b 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.