IRAK-M Promotes Alternative Macrophage Activation and Fibroproliferation in Bleomycin-Induced Lung Injury
| العنوان: | IRAK-M Promotes Alternative Macrophage Activation and Fibroproliferation in Bleomycin-Induced Lung Injury |
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| المؤلفون: | Michael W. Newstead, Xiaokui M. Mo, Richard A. Flavell, Bethany B. Moore, Theodore J. Standiford, Steven L. Kunkel, Xianying Zeng, Urvashi Bhan, Megan N. Ballinger, John W. Christman |
| المصدر: | The Journal of Immunology. 194:1894-1904 |
| بيانات النشر: | The American Association of Immunologists, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Male, Blotting, Western, Immunology, Enzyme-Linked Immunosorbent Assay, Inflammation, Cell Separation, Biology, Lung injury, Real-Time Polymerase Chain Reaction, Bleomycin, Article, Extracellular matrix, Mice, chemistry.chemical_compound, Idiopathic pulmonary fibrosis, Fibrosis, Pulmonary fibrosis, medicine, Animals, Humans, Immunology and Allergy, Mice, Knockout, Antibiotics, Antineoplastic, Lung, Fibroblasts, Macrophage Activation, medicine.disease, Coculture Techniques, Idiopathic Pulmonary Fibrosis, Mice, Inbred C57BL, Disease Models, Animal, Interleukin-1 Receptor-Associated Kinases, medicine.anatomical_structure, chemistry, Cancer research, Female, Collagen, medicine.symptom, Transcriptome |
| الوصف: | Idiopathic pulmonary fibrosis is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with pulmonary fibrosis. Although previous studies focused on structural cells in promoting fibrosis, our study assessed the contribution of macrophages. Recently, TLR signaling has been identified as a regulator of pulmonary fibrosis. IL-1R–associated kinase-M (IRAK-M), a MyD88-dependent inhibitor of TLR signaling, suppresses deleterious inflammation, but may paradoxically promote fibrogenesis. Mice deficient in IRAK-M (IRAK-M−/−) were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with reduced production of IL-13 compared with wild-type (WT) control mice. Bone marrow chimera experiments indicated that IRAK-M expression by bone marrow–derived cells, rather than structural cells, promoted fibrosis. After bleomycin, WT macrophages displayed an alternatively activated phenotype, whereas IRAK-M−/− macrophages displayed higher expression of classically activated macrophage markers. Using an in vitro coculture system, macrophages isolated from in vivo bleomycin-challenged WT, but not IRAK-M−/−, mice promoted increased collagen and α-smooth muscle actin expression from lung fibroblasts in an IL-13–dependent fashion. Finally, IRAK-M expression is upregulated in peripheral blood cells from idiopathic pulmonary fibrosis patients and correlated with markers of alternative macrophage activation. These data indicate expression of IRAK-M skews lung macrophages toward an alternatively activated profibrotic phenotype, which promotes collagen production, leading to the progression of experimental pulmonary fibrosis. |
| تدمد: | 1550-6606 0022-1767 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aab8e066812bec946168ae2f60653c53 https://doi.org/10.4049/jimmunol.1402377 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....aab8e066812bec946168ae2f60653c53 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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