2. Academic Validation
  3. Genetic deficiency of the transcription factor NFAT1 confers protection against fibrogenic responses independent of immune influx

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.
Ragini Vittal 1,  Natalie M Walker 2,  A Patrick McLinden 3,  Russell R Braeuer 2,  Fang Ke 2,  Fatemeh Fattahi 2,  Michael P Combs 2,  Keizo Misumi 2,  Yoshiro Aoki 2,  David S Wheeler 2,  Carol A Wilke 4,  Steven K Huang 5,  Bethany B Moore 6,  Pengxiu Cao 7,  Vibha N Lama 8
Affiliations

Affiliations

  • 1 Internal Medicine/PULM, Emory University, Ann Arbor, MI, United States.
  • 2 Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
  • 3 Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, United States.
  • 4 Department of Microbiology and Immunology, University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
  • 5 University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
  • 6 Internal Medicine, University of Michigan-Ann Arbor, Ann Arbor, MI, United States.
  • 7 Key Laboaratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, University of Michigan, Shijiazhuang, Hebei, China.
  • 8 Division of Pulmonary and Critical Care, Department of Internal Medicine, Emory University, Ann Arbor, MI, United States.
PMID: 37933452 DOI: 10.1152/ajplung.00045.2023
Abstract

Idiopathic 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 bleomycin in vivo and MCs derived from Nfat1-/- mice demonstrated decreased ATX expression and migration in vitro. Human IPF MCs demonstrated constitutive NFAT1 activation, and regulation of ATX in these cells by NFAT1 was confirmed utilizing pharmacologic and genetic inhibition. Our findings identify NFAT1 as a critical mediator of pro-fibrotic processes contributing to dysregulated lung remodeling and suggest its targeting in MCs as a potential therapeutic strategy in IPF.

Keywords

Autotaxin; NFAT1; PDGFR alpha positive mesenchymal cells; fibrosis; migration.

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