Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Zyulina, V.
Role of microRNA-424(322)/503 in epidermal Langerhans cell
and monocyte-derived dendritic cell differentiation
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2021. pp. 104
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Stradner Martin Helmut
- Strobl Herbert
- Altmetrics:
- Abstract:
- MicroRNAs are small non-coding RNAs, which regulate key biological processes in immune cells and define their phenotype and functions. Deficiency of Dicer, an enzyme critical for microRNA processing, in murine CD11c+ cells revealed dysregulated dendritic cell (DC) development and function. However, the implication of individual microRNAs in the process of DC differentiation remains poorly understood. Therefore, we focused our studies on the molecular mechanisms regulated by specific microRNAs in DC subset specification. Our group previously searched for the microRNAs that are differentially expressed by human DC subsets. We identified that miR-424(322)/503 is strongly upregulated in pro-inflammatory monocyte –derived dendritic cells (moDCs) in comparison to anti-inflammatory Langerhans cells (LCs). Using lentiviral gain- and loss-of-function approach we confirmed that miR-424(322)/503 is critical for moDC development. Conversely, LCs were unaffected by the miR-424(322)/503 deficiency. We identified that miR-424(322)/503 is required for moDC differentiation. To determine whether miR-424/503 is also involved in molecular mechanisms of moDCs differentiation in vivo, we subjected miR-424(322)/503 (miR-KO) mice to a clinically relevant model of psoriasis-like skin inflammation. We observed that moDCs subsets were significantly reduced in the dermis of miR-KO mice under inflammatory conditions in comparison with the WT mice. However, DC-precursors in the fresh isolated bone marrow were equally present in both conditions. Similarly, the percentage of ex vivo differentiated bone marrow - derived DCs (BMDCs) was diminished in miR-KO mice. Consequently, our murine data corroborate our findings in human moDC vs. LC differentiation that moDCs development was selectively dependent on miR-424(322)/503. Finally, we characterized the transcriptional profile of BMDCs generated from miR-KO mice and found TGF-β signature genes to be upregulated in miR-KO cells. Consistent with that, loss of miR-424(322)/503 facilitated TGF-β1-dependent LC differentiation at the expense of moDC differentiation. Thereby, we proposed a model where miR-424(322)/503 acts as a molecular switch for LCs vs. moDCs cell fate lineage decision via modulating TGF-β signaling. Our findings substantiate the pivotal role of miR-424(322)/503 in moDCs differentiation both in vitro and in vivo. In the study we provided several novel insights into the mechanisms underlying differentiation of two functionally different DC subsets (moDCs and LCs) from the common monocytic precursor.