Medizinische Universität Graz - Research portal
Selected Publication:
Lang, M.
TGF-β family signaling controlling DC phenotype and subset specification in Inflammation and Langerhans Cell Histiocytosis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 107
[OPEN ACCESS]
FullText
- Authors Med Uni Graz:
- Advisor:
- Madl Tobias
- Strobl Herbert
- Altmetrics:
- Abstract:
- Langerhans Cells (LCs) as members of the Dendritic cell (DC) family are specialized antigen presenting cells (APC) and sentinels of the immune system localized at the outermost layer of the skin. Thus, the phenotypic appearance and function of DCs and LCs is strongly influenced by molecular and microenvironmental changes. The TGF-β signaling pathway is highly conserved across species and is crucially implicated in various of biological processes. For keeping immunoregulatory processes in balance, tight regulation is necessary. Aberrations in components of the TGF-β family signaling cascade are found in inflammatory diseases or malignancies. TGF-β can act through classical TGF-β type I receptor (ALK5) leading to the activation of phospho-SMAD2,3 or through BMPR1a signaling (ALK3) upstream of phospho- SMAD1,5,8. The present thesis covers two main questions. The first objective was the investigation of how microenvironmental signals influence DC function and phenotype in inflamed tissues. Specifically, we investigated the neo-appearing CD1c+CLEC10A+ DC phenotype and its relationship to classical LCs in psoriasis vulgaris, which represents a presumed immune-system related inflammatory skin disease, showing strong upregulation of TGF-β family member BMP7. In addition to human patient biopsies, we mechanistically investigated the plasticity of blood CD1c+ DCs (cDC2s) by using CD34+ hematopoietic progenitor cells, peripheral blood cell fractions and transcriptomic data analysis. We found that BMPR1a and TGFβR co-signaling, both activated in the inflamed skin, induce an Axl+CD1c+ phenotype from CD34+ progenitor cells and blood cDC2s, and is similar present in the human psoriatic skin. Furthermore, inhibition of inflammation-associated p38MAPK signaling led to the conversion of a TGF-β1-induced RelB+cDC2 phenotype to RelB-LCs. Additionally, we propose a serum-free, defined differentiation model by use of BMP7 and TGF-β1, which enables the parallel generation of CD34+ progenitor cell-derived cDC2-and LC-like cells. The second objective was to investigate the role of TGF-β signaling and its interplay with Notch signaling in the course of BRAFV600E-Langerhans Cell Histiocytosis (LCH). By use of BRAFV600E modified progenitor cells we thoroughly compared differences in the signal requirements during LC/LCH-like cell differentiation. We found that the BRAFV600E mutation promotes a monocyte differentiation and critically depends on Notch signaling for converting these monocytic cells into LCH cells. We delineated two signal cascades driving localized vs systemic LCH. BMPR1a signaling induced the localized, mono/oligo focal E-cadherin+ LCH phenotype whereas classical TGF-β1 signaling promoted multi-systemic histiocytosis. Moreover, we observed that BRAFV600E progenitor cells as well as primary patient biopsies show activation of components of the TGF-β family signaling. Additionally, we showed that inhibition of non-canonical NFkB transcription factor RelB in BRAFV600E progenitor cells diminishes the mutation driven monocytic phenotype, suggesting a potential therapeutic target.