Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Schnoegl, D.
Innate Immunity in pulmonary hypertension associated with chronic lung diseases
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Stradner Martin Helmut
- Wadsack Christian
- Altmetrics:
- Abstract:
- Activator protein 1 (AP-1) transcription factors are important for regulation of many cellular processes such as proliferation, apoptosis, differentiation, and inflammation. Both, overexpression and knock-out of single AP-1 components in mice lead to severe phenotypes. In humans, increased AP-1 levels have been reported in patients suffering from systemic sclerosis (SSc) and cancer, diseases associated with altered numbers and functions of natural killer (NK) cells. Both inhibiting and enhancing effects of AP-1 on NK cell proliferation and function have been reported and both, modulation of AP-1 and NK cell activity, could offer novel therapeutic strategies. In this study we used mice, overexpressing one of the AP-1 members Fra-2 (transgenic, TG), the c-fos/AP-1-inhibitor T-5224 and CRISPR/Cas9-mediated knock-out of individual AP-1 components to investigate their effects on NK cells. We show increased sensitivity to low IL-15 concentrations and decreased survival and proliferation of T-5224 treated NK cells. Fra-2 TG mice develop a SSc-like phenotype and show reduced NK cell numbers before disease onset, highlighting the importance of functional NK cells in vivo. Examination of NK cell precursors revealed a cell intrinsic developmental defect in TG mice beginning at the pre natural killer cell progenitor (preNKP) stage due to a significantly decreased expression of the Nfil3 transcription factor. The presence of an AP-1 binding site in the promotor of Nfil3 possibly explains its reduction. The remaining transgenic NK cells were defective, exhibiting decreased maturity, proliferation, and in vitro cytotoxicity, compared to wild type (WT) cells. In conclusion, our data demonstrates that correct expression and regulation of AP-1 is essential for NK cell development, survival, and function. Additionally, preliminary NK cell transfer experiments of healthy NK cells to Fra-2 TG mice, suggested that restoration of NK cells can ameliorate the development of SSc associated pulmonary hypertension, potentially by reducing the senescent load in the blood vessels but does not affect lung function of Fra-2 TG mice. Analysis of human lung tissue, revealed decreased abundance of NK cells in patients suffering from pulmonary fibrosis and high levels of Fra-2 expression in these cells, indicating that this mechanism might be conserved across species.