Collagen-producing macrophages can mediate lung fibrosis throughFra-2/AP-1 expression
| Autor: | Alvaro C. Ucero, C Fustero-Torre, Erwin F. Wagner, P Ximenez-Embun, A Hernandez, Latifa Bakiri, Masakatsu Suzuki |
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| Rok vydání: | 2018 |
| Předmět: |
Cell type
Innate immune system business.industry respiratory system medicine.disease Bleomycin respiratory tract diseases 03 medical and health sciences Idiopathic pulmonary fibrosis chemistry.chemical_compound 0302 clinical medicine Immune system medicine.anatomical_structure 030228 respiratory system chemistry In vivo Fibrosis medicine Cancer research 030212 general & internal medicine Fibroblast business |
| Zdroj: | Mechanisms of Lung Injury and Repair. |
| Popis: | Lung fibrosis is a lethal scarring process characterized by progressive matrix accumulation. Fibrosis can be induced experimentally in mice by Bleomycin administration or by broad transgenic expression of the AP-1 transcription factor Fra-2 (Fra-2tg). RNA-seq on lungs from Fra-2tg mice before fibrosis develops revealed significantly increased expression of collagens as well as genes controlling innate immunity. Fra-2 protein expression is found in several cell types in human and mouse fibrotic lungs, including myeloid cells, while barely detectable in healthy tissue. Specific genetic deletion of Fra-2 in myeloid cells prevents Bleomycin-induced lung fibrosis. In vitro and in vivo experiments suggest that Fra-2 controls the pro-fibrogenic activity of macrophages, rather than the immune response. These findings are clinically relevant since pharmacological inhibition of Fra-2/AP-1 activity demonstrated therapeutic efficacy against lung fibrosis progression. In addition, type VI collagen expression from macrophages was associated with Fra-2 expression, fibroblast activation and the extent of lung fibrosis in different experimental models. Proteomic analyses identified type VI collagen only in exosomes isolated from bronchioalveolar lavage of fibrotic mice. Finally, FOSL2 (encoding Fra-2) and COL6A3 were co-increased in the lungs of idiopathic pulmonary fibrosis (IPF) patients compared to healthy or chronic obstructive pulmonary disease patients. Therefore, the expression of type VI collagen and Fra-2 in macrophages may serve as a biomarker and a promising therapeutic option for IPF and possibly other fibrotic diseases, since both genes seem important modulators of lung fibrosis development. |
| Databáze: | OpenAIRE |
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