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

Our plain-English summary of Lrp5/β-Catenin Signaling Controls Lung Macrophage Differentiation and Inhibits Resolution of Fibrosis, by J.A. Sennello, A.V. Misharin, A.S. Flozak, et al (American Journal of Respiratory Cell and Molecular Biology, 2017).

The study

• Authors: J.A. Sennello, A.V. Misharin, A.S. Flozak, S. Berdnikovs, P. Cheresh, J. Varga, D.W. Kamp, G.R. Budinger, C.J. Gottardi, A.P. Lam
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2017;56(2):191-201
• Cited by: 56 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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 Flow alveolar macrophages, a cell type previously implicated as positive effectors of fibrosis. Macrophage-specific deletion of β-catenin in CD11ccre;β-cateninflox 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 CD11ccre;β-cateninflox 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.

In plain English

In these laboratory experiments at Northwestern University in Chicago, the authors studied how a signaling pathway (Wnt/β-catenin, working through a receptor called Lrp5) affects lung scarring (fibrosis) and immune cells called macrophages in mice. Scarring was caused by the drug bleomycin or by one dose of 200 µg of crocidolite asbestos put into the windpipe. Titanium dioxide was the comparison particle. Twenty-one days after bleomycin, mice lacking Lrp5 had fewer of one type of recruited alveolar macrophage (0.61 versus 1.02 million cells per lung). Mice lacking β-catenin in CD11c-bearing cells developed similar scarring at 6 and 21 days but showed better resolution at 8 weeks. After asbestos, mice lacking Lrp5 had collagen build-up at 3 weeks similar to normal mice, but markedly less by 8 weeks. Lithium chloride, used to switch the pathway on, increased lung collagen in normal mice given bleomycin. The authors concluded that this signaling leads to an alveolar macrophage type that works against the resolution of fibrosis. They noted that dendritic cells, which also carry CD11c, may have contributed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiments in genetically modified and wild-type mice, with lungs injured by bleomycin or asbestos, plus cell-culture work
• Who was studied: Age- and sex-matched laboratory mice, 8 to 12 weeks old. These included mice lacking Lrp5, mice lacking β-catenin in CD11c-bearing cells, Axin2 reporter mice and wild-type C57BL/6 mice, at Northwestern University, Chicago. Group sizes in the figure legends range from 3 to 9 animals per condition. Dates are not given.
• Exposure: Asbestos experiments: 200 µg of UICC crocidolite asbestos given into the windpipe, with titanium dioxide as the control particle. Other experiments: a single intratracheal dose of bleomycin (1.5 U/kg), and daily 200 mg/kg lithium chloride injections into the abdomen to activate β-catenin signaling.
• Main results:
  • 14 days after bleomycin, 75 genes differed in expression between the lungs of mice lacking Lrp5 and normal mice. In a second group of mice, Lox and Mmp13 expression were increased in Lrp5-lacking lungs (3.9±1.0 fold versus 1.0±0.3 fold for Lox; 5.8±2.0 fold versus 1.1±0.2 fold for Mmp13).
  • In reporter mice, β-catenin signaling was detected in lung myeloid cells, particularly alveolar macrophages, interstitial macrophages and monocytes.
  • At day 21 after bleomycin, total immune (CD45+) cell numbers did not differ significantly between normal and Lrp5-lacking mice (14.2±1.5 versus 11.6±1.3 million cells per lung).
  • At day 21 after bleomycin, monocyte-derived (Siglec F low) alveolar macrophages were significantly lower in Lrp5-lacking mice: 0.61±0.12 versus 1.02±0.11 million cells per lung (n=5 animals per condition). By day 56 there were no differences in these macrophage populations.
  • In mice lacking β-catenin in CD11c-bearing cells, lung collagen and lavage-fluid protein after bleomycin did not differ from littermates at day 6 or day 21.
  • At 8 weeks after bleomycin, mice lacking β-catenin in CD11c-bearing cells showed improved resolution of fibrosis compared with littermates (n=4-5 mice per condition).
  • After intratracheal crocidolite asbestos, mice lacking Lrp5 had increased collagen deposition at 3 weeks, similar to asbestos-treated normal mice (n=4-5 mice per condition).
  • By 8 weeks after asbestos, collagen deposition was markedly decreased in mice lacking Lrp5 compared with normal mice. Numerical values are given only in figures not included in the text.
  • At 8 weeks after asbestos, macrophage populations did not differ between normal and Lrp5-lacking mice.
  • In wild-type mice given bleomycin, daily lithium chloride increased collagen deposition and injury at 3 weeks. When given during weeks 2 and 3, it led to more collagen at 8 weeks than in control-treated mice (n=3-6 mice per condition).
• The authors' conclusion: The authors concluded that their data suggest lung myeloid cells respond to Lrp5/β-catenin signaling, leading to the development of an alveolar macrophage subtype that works against the resolution of lung fibrosis.
• Limitations the authors state:
  • CD11c is also found on lung dendritic cells, so a contribution from dendritic cells to the results in the CD11c-targeted mice cannot be completely excluded.
  • Whether the effects of β-catenin signaling in macrophages act within the macrophages themselves or through interactions with other lung cells requires further investigation.

Topics

Medical terms in this study, explained in our Lexicon: Macrophage, Fibrosis, Alveolar Macrophage.

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