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Autocrine lysophosphatidic acid signaling activates β-catenin and promotes lung allograft fibrosis
Pengxiu Cao, … , Eric R. Fearon, Vibha N. Lama
Pengxiu Cao, … , Eric R. Fearon, Vibha N. Lama
Published February 27, 2017
Citation Information: J Clin Invest. 2017;127(4):1517-1530. https://doi.org/10.1172/JCI88896.
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Research Article Cell biology Transplantation

Autocrine lysophosphatidic acid signaling activates β-catenin and promotes lung allograft fibrosis

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Abstract

Tissue fibrosis is the primary cause of long-term graft failure after organ transplantation. In lung allografts, progressive terminal airway fibrosis leads to an irreversible decline in lung function termed bronchiolitis obliterans syndrome (BOS). Here, we have identified an autocrine pathway linking nuclear factor of activated T cells 2 (NFAT1), autotaxin (ATX), lysophosphatidic acid (LPA), and β-catenin that contributes to progression of fibrosis in lung allografts. Mesenchymal cells (MCs) derived from fibrotic lung allografts (BOS MCs) demonstrated constitutive nuclear β-catenin expression that was dependent on autocrine ATX secretion and LPA signaling. We found that NFAT1 upstream of ATX regulated expression of ATX as well as β-catenin. Silencing NFAT1 in BOS MCs suppressed ATX expression, and sustained overexpression of NFAT1 increased ATX expression and activity in non-fibrotic MCs. LPA signaling induced NFAT1 nuclear translocation, suggesting that autocrine LPA synthesis promotes NFAT1 transcriptional activation and ATX secretion in a positive feedback loop. In an in vivo mouse orthotopic lung transplant model of BOS, antagonism of the LPA receptor (LPA1) or ATX inhibition decreased allograft fibrosis and was associated with lower active β-catenin and dephosphorylated NFAT1 expression. Lung allografts from β-catenin reporter mice demonstrated reduced β-catenin transcriptional activation in the presence of LPA1 antagonist, confirming an in vivo role for LPA signaling in β-catenin activation.

Authors

Pengxiu Cao, Yoshiro Aoki, Linda Badri, Natalie M. Walker, Casey M. Manning, Amir Lagstein, Eric R. Fearon, Vibha N. Lama

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Figure 1

Increased MC β-catenin expression in fibrotic human lung allografts.

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Increased MC β-catenin expression in fibrotic human lung allografts.
(A ...
(A and B) Collagen I and β-catenin protein levels in MCs derived from lung allografts with and without BOS were analyzed by immunoblotting. Mean ± SEM (n = 8/group). P values were obtained by unpaired t test. The collagen I antibody recognizes both chains of α1 and α2. (C) Correlation of total β-catenin and collagen I protein expression in individual patient-derived MCs is shown (P < 0.0001 determined by 2-tailed test; r2 = 0.7310 obtained by correlation). Non-BOS MCs (gray dots, n = 8), BOS MCs (black dots, n = 8). (D) Nuclear fraction of β-catenin in BOS and non-BOS MCs was measured by immunoblotting. Mean ± SEM (n = 5/group) with unpaired t test. (E) Representative images of β-catenin and α-SMA immunohistochemical staining of histological sections demonstrating BO. H&E and trichrome staining demonstrate a tangentially cut, completely obliterated bronchus. Myofibroblasts in the fibrous plug in the lumen of the bronchus are recognized by positive α-SMA immunohistochemical staining (brown DAB). Overlapping of β-catenin staining with hematoxylin blue nuclear stains was noted in these MCs. Scale bars: 20 μm. (F) Expression of β-catenin contributes to fibrotic functions of BOS MCs. BOS MCs were transfected with β-catenin siRNA or scrambled siRNA, and protein expression was measured by immunoblotting (n = 5/group). **P < 0.01, ***P < 0.001, ****P < 0.0001.
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