Genetic deficiency of the transcription factor NFAT1 confers protection against fibrogenic responses independent of immune influx

Am J Physiol Lung Cell Mol Physiol. 2023 Nov 7. doi: 10.1152/ajplung.00045.2023. Online ahead of print.ABSTRACTIdiopathic pulmonary fibrosis (IPF) is marked by unremitting matrix deposition and architectural distortion. Multiple pro-fibrotic pathways contribute to the persistent activation of mesenchymal cells (MCs) in fibrosis, highlighting the need to identify and target common signaling pathways. The transcription factor NFAT1 (nuclear factor of activated T cells 1) lies downstream of second messenger calcium signaling and has been recently shown to regulate key pro-fibrotic mediator autotaxin (ATX) in lung MCs. Herein, we investigate the role of NFAT1 in regulating fibroproliferative responses during the development of lung fibrosis. Nfat1-/- deficient mice subjected to bleomycin injury demonstrated improved survival, and protection from lung fibrosis and collagen deposition as compared to bleomycin-injured wildtype (WT) mice. Chimera mice, generated by reconstituting bone marrow cells from WT or Nfat1-/- mice into irradiated WT mice (WTàWT and Nfat1-/-àWT), demonstrated no difference in bleomycin-induced fibrosis, suggesting immune influx-independent fibro-protection in Nfat1-/- mice. Examination of lung tissue and flow sorted lineageneg/PDGFRαpos MCs demonstrated decreased MC numbers, proliferation (cyclin D1 and EdU incorporation), myofibroblast differentiation (αSMA), and survival (Birc5) in Nfat1-/- mice. Nfat1 deficiency abrogated ATX expression in response to b...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - Category: Cytology Authors: Source Type: research