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Systems Immunology Identifies the Combined Activity of a Set of MicroRNAs in Shaping the Th2 Phenotype in Allergic Airway Inflammation

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A7363 - Systems Immunology Identifies the Combined Activity of a Set of MicroRNAs in Shaping the Th2 Phenotype in Allergic Airway Inflammation
Author Block: A. Kilic1, M. Santolini2, T. Nakano3, M. Schiller4, M. Teranishi5, P. Gellert6, Y. Ponomareva7, S. Uchida7, T. Braun5, S. T. Weiss1, A. Sharma1, H. Renz3; 1Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, United States, 2Center for Complex Network Research (CCNR), Northeastern University, Boston, MA, United States, 3Institute of Laboratory Medicine, Philipps University Marburg, Marburg, Germany, 4Clinic for Dermatology and Venereology, University Medical Center Rostock, Rostock, Germany, 5Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany, 6Breast Cancer Now Research Centre at The Institute of Cancer Research, London, United Kingdom, 7Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany.
RATIONALE: The inflammatory response in allergic asthma is dominated by a CD4+ T helper 2 (Th2) cell signature and amplified in self-enforcing loops, leaving the host unable to terminate the immune reaction and leading to distress in patients. Deregulated expression of microRNAs (miRNAs) has been associated with various disease conditions, including asthma. Whether miRNAs stabilize the Th2 population in the allergic inflamed lung is not well understood and raise the need for deeper analysis.
METHODS:
Using well established mouse models of ovalbumin-induced chronic airway inflammation in combination with FACS-sorting, distinct Th2 cells were isolated from chronic inflamed lung tissue and subjected to microarray analyses (mRNA and microRNA). Naïve T cells from sham immunized and sham treated mice were used as a control population. A multi-omics network approach, Integration of Differential Expression Across Layers of multi-omics (IDEAL), was developed, integrating gene and microRNA information and inferring the protein information from the human interactome. Predictions were validated in HEK293T cells and mouse CD4+ T cells in the in vitro system of differentiating Th2-cells.
RESULTS: Microarray results revealed the differential expression of 137 miRNAs in ex vivo Th2 chronic cells compared to naïve CD4+ T cells, with the majority of miRNA being downregulated in Th2 cells. Using a network approach, we assessed the consequences of differentially expressed miRNAs on the molecular interactome and identified the collective activity of 5 miRNA exerting the biggest perturbation on the interactome, by targeting hub genes. We validated target predictions on hub genes with 3’-UTR-luciferase assays in HEK293T cells analyzing wildtype and mutated 3’-UTR-sequences in vitro. The importance of these miRNAs (mir27b, mir206, mir106b, mir203, and mir23b) on Th2 cell function was proven by sequentially introducing inhibitors and/or mimics and thereby antagonizing the predictions. This resulted in an alleviated phenotype in mouse Th2 cells in vitro.
CONCLUSIONS: A systems immunology tool, able to identify and rank the impact of miRNA on the molecular interactome, was developed and validated. With this, a miRNA network stabilizing Th2 cells in chronic allergic airway inflammation was identified. Thus, this result may open the opportunity for novel approaches of therapeutic intervention.
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