| Autor: |
Sennello JA; 1 Division of Pulmonary and Critical Care Medicine., Misharin AV; 1 Division of Pulmonary and Critical Care Medicine., Flozak AS; 1 Division of Pulmonary and Critical Care Medicine., Berdnikovs S; 2 Division of Allergy and Immunology, and., Cheresh P; 1 Division of Pulmonary and Critical Care Medicine., Varga J; 3 Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Kamp DW; 1 Division of Pulmonary and Critical Care Medicine., Budinger GR; 1 Division of Pulmonary and Critical Care Medicine., Gottardi CJ; 1 Division of Pulmonary and Critical Care Medicine., Lam AP; 1 Division of Pulmonary and Critical Care Medicine. |
| Jazyk: |
angličtina |
| Zdroj: |
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2017 Feb; Vol. 56 (2), pp. 191-201. |
| DOI: |
10.1165/rcmb.2016-0147OC |
| Abstrakt: |
Previous studies established that attenuating Wnt/β-catenin signaling limits lung fibrosis in the bleomycin mouse model of this disease, but the contribution of this pathway to distinct lung cell phenotypes relevant to tissue repair and fibrosis remains incompletely understood. Using microarray analysis, we found that bleomycin-injured lungs from mice that lack the Wnt coreceptor low density lipoprotein receptor-related protein 5 (Lrp5) and exhibit reduced fibrosis showed enrichment for pathways related to extracellular matrix processing, immunity, and lymphocyte proliferation, suggesting the contribution of an immune-matrix remodeling axis relevant to fibrosis. Activation of β-catenin signaling was seen in lung macrophages using the β-catenin reporter mouse, Axin2 +/LacZ . Analysis of lung immune cells by flow cytometry after bleomycin administration revealed that Lrp5 -/- lungs contained significantly fewer Siglec F low alveolar macrophages, a cell type previously implicated as positive effectors of fibrosis. Macrophage-specific deletion of β-catenin in CD11c cre ;β-catenin flox mice did not prevent development of bleomycin-induced fibrosis but facilitated its resolution by 8 weeks. In a nonresolving model of fibrosis, intratracheal administration of asbestos in Lrp5 -/- mice also did not prevent the development of fibrosis but hindered the progression of fibrosis in asbestos-treated Lrp5 -/- lungs, phenocopying the findings in bleomycin-treated CD11c cre ;β-catenin flox mice. Activation of β-catenin signaling using lithium chloride resulted in worsened fibrosis in wild-type mice, further supporting that the effects of loss of Lrp5 are directly mediated by Wnt/β-catenin signaling. Together, these data suggest that lung myeloid cells are responsive to Lrp5/β-catenin signaling, leading to differentiation of an alveolar macrophage subtype that antagonizes the resolution of lung fibrosis. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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