Mesenchymal Cell Dysfunction in Fibroproliferative Lung Disease

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Abstract Progressive fibrosis is a cause of major morbidity and mortality as best exemplified by idiopathic pulmonary fibrosis (IPF). The molecular mechanisms that control unremitting lung fibrosis remain poorly understood. During the funding period of this PO1, we identified an invasive fibroblast phenotype that appears to be an important feature of unremitting pulmonary fibrosis. We have identified invasive fibroblasts that contribute to severe lung fibrosis in mouse and human, and the invasive phenotype requires HAS2, CD44, and beta-arrestins. Fibroblast lineage-tracing studies identified that T box gene 4 (Tbx4)-lineage mesenchymal progenitors are the predominant source of myofibroblasts in injured adult murine lung. To further analyze the genetic regulation of fibroblast invasion, we performed RNA-seq analysis of a set of invasive and noninvasive fibroblast samples from IPF patients. Unexpectedly, we found that several immune molecules including both checkpoint PD1 ligands, PD-L1 (CD274) and PD-L2 (CD273), are significantly upregulated preferentially on invasive human fibroblasts. The Programmed Death-1 (PD-1, CD279) pathway is a homeostatic mechanism of the immune system that prevents autoimmunity and uncontrolled inflammation, and it is also used by cancer cells to escape from immune surveillance. This is an intriguing and novel discovery, particularly in light of the FDA approval of the multi- tyrosine kinase inhibitor nintedanib for IPF, a drug that was initially developed for cancer. A paradigm has evolved that the pathobiology of IPF is more similar to cancer than to chronic inflammation. However, the role of PD- 1/PD-L1 in lung fibrosis is unknown. Our preliminary studies revealed that PD-L1 regulates fibroblast adhesion, migration and invasiveness. We found that the focal adhesion components including focal adhesion kinase (FAK) and Rho/ROCK are significantly up-regulated. More recently, in collaboration with Dr. John Belperio at UCLA, PI on Project 3, we have also identified invasive fibroblasts in patients suffering from chronic lung allograft dysfunction (CLAD), which is the major cause of morbidity and mortality following lung transplantation. We propose to perform a similar approach in these cells with the hope of identifying new targets for therapy of CLAD. We have begun to examine the regulation of PD-L1 and found that PD-L1 was down-regulated by p53 in lung fibroblasts. In contrast to the immune checkpoint genes, p53 is markedly down-regulated in invasive fibroblasts, similar to that in cancer cells. Much attention has been paid to epithelial p53 expression and function in fibrosis, but the role of p53 in fibroblasts has not been thoroughly investigated. It appears that p53 may have a role not only in preventing epithelial apoptosis, but also in fibroblast invasiveness, thereby providing two distinct mechanisms in the pathogenesis of pulmonary fibrosis. Taken together, we hypothesize that loss of p53 up- regulates immune checkpoint genes in lung fibroblasts, leading to the activation of PD-1 ligand-mediated evasion of immune detection, focal adhesion and cell invasiveness.