title: GM-CSF but not IL-17 is critical for the development of severe interstitial lung disease in SKG mice.
abstract: Interstitial lung disease (ILD) is a common complication and sometimes a prognostic factor of connective tissue diseases (CTDs) in humans. However, suitable animal model of severe CTD-associated ILD (CTD-ILD) has been limited. In this study, we showed that zymosan-treated SKG mice developed not only arthritis but also chronic-progressive ILD with high mortality over several months. The pathological and clinical features of ILD in zymosan-treated SKG mice were similar to that of human severe CTD-ILD. ILD in this mouse was characterized by massive infiltration of Th17 cells, GM-CSF-producing CD4(+) T cells, and CD11b(+) Gr1(+) neutrophils with fibrosis. Naive SKG T cells were skewed to differentiate into GM-CSF-producing cells, and GM-CSF secreted by T cells enhanced IL-6 and IL-1β production by macrophages, which in turn enhanced differentiation of IL-17A- and/or GM-CSF-producing T cells and infiltration of neutrophils into lung. Neutralization of GM-CSF completely blocked the development of this ILD, and the blocking of IL-6 signaling resulted in partial prevention of it, whereas neutralization of IL-17A did not. In contrast, the progression of arthritis was inhibited by the neutralization of GM-CSF and slightly by the neutralization of IL-17A, but not by the blocking of IL-6 signaling. These data suggested zymosan-treated SKG mice could be a useful mouse model of severe CTD-ILD, and GM-CSF, rather than IL-17A or IL-6, contributed to the development of ILD in zymosan-treated SKG mice, indicating that neutralization of GM-CSF would be a useful therapeutic strategy for severe CTD-ILD.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Aoi
authors.initials: A
authors.lastname: Shiomi
authors.affiliation: Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan takausui@kuhp.kyoto-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
authors.affiliation: Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kosaku
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D001168:Arthritis / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003240:Connective Tissue Diseases / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D015054:Zymosan; D000093242:Interleukin-6 Inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D015054:Zymosan; D000093242:Interleukin-6 Inhibitors