Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis.
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.
Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle Upon Tyne, UK.|Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
L A
LA
Borthwick
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
L
L
Barron
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
K M
KM
Hart
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
K M
KM
Vannella
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
R W
RW
Thompson
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
S
S
Oland
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
A
A
Cheever
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
J
J
Sciurba
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
T R
TR
Ramalingam
Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle Upon Tyne, UK.|Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne, UK.
A J
AJ
Fisher
Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
T A
TA
Wynn
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D005355:Fibrosis; D005786:Gene Expression Regulation; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009559:Nippostrongylus / Q000276:immunology / Q000472:pathogenicity; D011014:Pneumonia / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D039981:Pyroglyphidae / Q000276:immunology; D012550:Schistosoma mansoni / Q000276:immunology / Q000472:pathogenicity; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D015398:Signal Transduction; D017206:Strongylida Infections / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000469:parasitology / Q000473:pathology
D000943:Antigens, Differentiation; D000950:Antigens, Ly; D039481:CD11b Antigen; D066257:Heparin-binding EGF-like Growth Factor; D018793:Interleukin-13; C494192:Ly-6C antigen, mouse; C036763:monocyte-macrophage differentiation antigen