Abstract
The roles of macrophages in type 2-driven inflammation and fibrosis remain unclear. Here, using CD11b-diphtheria toxin receptor (DTR) transgenic mice and three models of interleukin 13 (IL-13)-dependent inflammation, fibrosis, and immunity, we show that CD11b(+) F4/80(+) Ly6C(+) macrophages are required for the maintenance of type 2 immunity within affected tissues but not secondary lymphoid organs. Direct depletion of macrophages during the maintenance or resolution phases of secondary Schistosoma mansoni egg-induced granuloma formation caused a profound decrease in inflammation, fibrosis, and type 2 gene expression. Additional studies with CD11c-DTR and CD11b/CD11c-DTR double-transgenic mice suggested that macrophages but not dendritic cells were critical. Mechanistically, macrophage depletion impaired effector CD4(+) T helper type 2 (Th2) cell homing and activation within the inflamed lung. Depletion of CD11b(+) F4/80(+) Ly6C(+) macrophages similarly reduced house dust mite-induced allergic lung inflammation and suppressed IL-13-dependent immunity to the nematode parasite Nippostrongylus brasiliensis. Consequently, therapeutic strategies targeting macrophages offer a novel approach to ameliorate established type 2 inflammatory diseases.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / immunology
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Antigens, Ly / genetics
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Antigens, Ly / immunology
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CD11b Antigen / genetics
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CD11b Antigen / immunology
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Fibrosis
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Gene Expression Regulation
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Heparin-binding EGF-like Growth Factor / genetics
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Heparin-binding EGF-like Growth Factor / immunology
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Interleukin-13 / genetics
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Interleukin-13 / immunology*
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Lung / immunology
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Lung / parasitology
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Lung / pathology
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Macrophages, Alveolar / immunology*
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Macrophages, Alveolar / parasitology
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Macrophages, Alveolar / pathology
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Mice
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Mice, Transgenic
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Nippostrongylus / immunology
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Nippostrongylus / pathogenicity
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Pneumonia / immunology*
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Pneumonia / parasitology
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Pneumonia / pathology
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Pyroglyphidae / immunology
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Schistosoma mansoni / immunology
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Schistosoma mansoni / pathogenicity
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Schistosomiasis mansoni / immunology*
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Schistosomiasis mansoni / parasitology
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Schistosomiasis mansoni / pathology
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Signal Transduction
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Strongylida Infections / immunology*
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Strongylida Infections / parasitology
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Strongylida Infections / pathology
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Th2 Cells / immunology*
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Th2 Cells / parasitology
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Th2 Cells / pathology
Substances
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Antigens, Differentiation
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Antigens, Ly
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CD11b Antigen
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Heparin-binding EGF-like Growth Factor
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Interleukin-13
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Ly-6C antigen, mouse
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monocyte-macrophage differentiation antigen