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

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.

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…If inflammation is not resolved, chronic activation of ATX-LPA-inflammatory signaling and the wound healing response becomes maladaptive [30,32] in diseases such as pulmonary fibrosis, cirrhosis, rheumatoid arthritis, inflammatory bowel disease, and cancers [24,48]. Many inflammatory conditions are accompanied by fibrosis, a process driven through LPAR1 signaling and further mediated through inflammatory cytokines [49][50][51][52][53][54][55][56][57][58][59][60][61]. This is why an ATX inhibitor, GLPG1690 [62] and an LPAR1 antagonist (BMS986020) [63] attenuated idiopathic pulmonary fibrosis in Phase IIa clinical trials.…”

“…Although the resulting loss of~10% of lung function may not be clinically significant, it could be avoided. LPAR1 activation drives fibrosis in liver and lungs [49][50][51][52][53][54][55][56][57][58][59][60]141] and it is likely to drive RT-induced fibrosis [30,124,142].…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…These grafts, which are discordant at the class I allele (H-2D b ) with the recipient, demonstrate an evolution from immune cell infiltration to epithelial cell injury and development of fibrosis over time that is reminiscent of human disease. The B6D2F1/J→DBA/2J transplant model also had very high penetrance, with 100% of allografts exhibiting fibrotic remodeling in the majority of airways, allowing it to be utilized for investigation of therapeutic targets (127). However, using this combination lends itself to the disadvantage that transgenic mice are not readily available on B6D2F1/J and DBA/2J genetic backgrounds.…”

In vitroinduction andin vivoengraftment of lung bud tip progenitor cells derived from human pluripotent stem cells

“…Injection of cells into the mouse trachea was performed as previously described (Badri et al, 2011;Cao et al, 2017). Briefly, animals were anesthetized and intubated.…”