Lrp5/β-Catenin Signaling Controls Lung Macrophage Differentiation and Inhibits Resolution of Fibrosis

Previous studies established that attenuating Wnt/beta-catenin signaling limits lung fibrosis in the bleomycinmouse 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 beta-catenin signaling was seen in lung macrophages using the beta-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 beta-catenin in CD11c(cre);beta-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);beta-catenin(flox) mice. Activation of beta-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/beta-catenin signaling. Together, these data suggest that lung myeloid cells are responsive to Lrp5/beta-catenin signaling, leading to differentiation of an alveolar macrophage subtype that antagonizes the resolution of lung fibrosis.