Abstract
Abstract It is likely that the continuous host response to a persistent challenge polarizes the cytokine environment toward a Th2 cytokine phenotype. We investigated the role of TLR9 in a Th2-driven pulmonary granulomatous response, initiated via the embolization of Schistosoma mansoni eggs to the lungs of mice. TLR9-/- mice showed an increase in pulmonary granuloma size, augmented collagen deposition, an increase in the Th2 cytokine phenotype, impaired accumulation of dendritic cells (DCs), and an increase in numbers of lung macrophages compared with WT mice. BM-derived DCs, but not macrophages, promoted the production of Th2 cytokines from CD4+ T cells during the S. mansoni egg antigen-induced immune response. In addition, DCs from TLR9-/- mice induced impaired Th1 cytokine (IFN-γ) and enhanced Th2 cytokine (IL-4, IL-5, and IL-13) compared with DCs from WT mice. Macrophages from TLR9-/- mice expressed significantly higher alternatively-activated (M2) phenotype characterized by increased "found in inflammatory zone-1" (FIZZ-1) expression. Passive immunization with neutralizing antibodies specific for FIZZ-1 during granuloma formation resulted in a decrease in granuloma size and collagen deposition. Together, these results suggest TLR9 plays an important role in the maintenance stage of specific chronic lung disorders. This work was supported by NIH grants P01-HL031963, HL092845, HL074024, and HL031237.
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