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Toll-like Receptor 9 Activation Is a Key Mechanism for the Maintenance of Chronic Lung Inflammation

¹ Department of Pathology, University of Michigan Medical School, Ann Arbor; ² Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor; and ³ Department of Pathology and Laboratory Medicine, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Steven L. Kunkel, Ph.D., Immunology Program, Department of Pathology, University of Michigan Medical School 4071 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. E-mail: slkunkel{at}umich.edu

Rationale: Accumulating evidence supports the hypothesis that the continuous host response to a persistent challenge can polarize the cytokine environment toward a Th2 cytokine phenotype, but the mechanisms responsible for this skewing are not clear.

Objectives: We investigated the role of Toll-like receptor 9 (TLR9) in a Th2-driven pulmonary granulomatous response initiated via the embolization of Schistosoma mansoni eggs to the lungs of mice.

Methods: Mice were intravenously injected with S. mansoni eggs. Histological and flow cytometric analysis, cytokine measurement, adoptive transfer of bone marrow (BM)-derived dendritic cells (DCs), and in vitro T-cell treatments with antigen-presenting cells were examined.

Measurements and Main Results: In comparison to wild-type mice, TLR9^–/– mice showed increased pulmonary granuloma size, augmented collagen deposition, increased Th2 cytokine phenotype, and impaired accumulation of DCs. BM-derived DCs, but not macrophages, recovered from animals with developed Th2-type lung granulomas promoted the production of type 2 cytokines from CD4⁺ T cells. BM-derived DCs from TLR9^–/– mice induced impaired Th1 cytokine and enhanced Th2 cytokine production by T cells, compared with DCs from WT mice. Macrophages from TLR9^–/– mice expressed a significantly higher alternatively activated (M2) phenotype characterized by increased "found in inflammatory zone-1" (FIZZ1) and arginase-1 expression. The adoptive transfer of BM-derived DCs from syngeneic WT mice into TLR9^–/– mice restored the granuloma phenotype seen in WT mice.

Conclusions: These studies suggest that TLR9 plays an important mechanistic role in the maintenance of the pulmonary granulomatous response.

Key Words: granuloma • pulmonary fibrosis • innate immunity • dendritic cell • macrophage

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject A number of studies have suggested that the innate immune response not only supports acute inflammation but also maintains the chronic inflammatory response. However, the mechanistic role of the innate immune response in the development of antigen-dependent chronic lung inflammation has not been well studied. What This Study Adds to the Field We demonstrate that the initiation and maintenance of chronic lung inflammation induced in Toll-like receptor 9–knockout mice is associated with an augmented granulomatous lung response, increased collagen deposition, skewed Th2 cytokine phenotype, impaired dendritic cell function, and activation of alternatively activated macrophages characterized by the production of "found in inflammatory zone-1" (FIZZ1).