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Identification of underlying molecular mechanisms of obesity-associated asthma
In the evolution of personalized medicine and stratified therapies, comprehensive understanding of the molecular mechanisms underlying different disease phenotypes, such as asthma phenotypes including obesity-associated asthma, are urgently needed. Biological pathways and functions of differentially...
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| Format: | Dissertation |
| Sprache: | Englisch |
| Veröffentlicht: |
Philipps-Universität Marburg
2021
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| Zusammenfassung: | In the evolution of personalized medicine and stratified therapies, comprehensive understanding of the molecular mechanisms underlying different disease phenotypes, such as asthma phenotypes including obesity-associated asthma, are urgently needed. Biological pathways and functions of differentially expressed genes and miRNAs can play an essential role in the development and severity of obesity-related asthma.
To fulfill this purpose, a preliminary work was initiated to establish optimal experimental conditions by investigating the effects related to different timings of CD4+ T cells processing from peripheral blood. Thus, 2 peripheral blood samples were drawn from each of 3 atopic patients and 3 healthy donors (12 samples), CD4+ T cells isolation was conducted from the first blood sample within two hours (Immediate) and from the second blood sample after 24 hours (Delayed), transcriptomic profiles of CD4+ T cells were examined using RNA-Seq analysis and readouts were verified on the epigenetic level through the H3K27ac ChIP-Seq analysis. After a successful establishment of ideal experimental conditions, peripheral blood was drawn from 10 obese, non-atopic asthmatic adults with a high body mass index (BMI; 36.67 ± 6.90), 10 non-obese, non- atopic asthmatic adults with normal BMI (23.88 ± 2.73), and 10 healthy controls with normal BMI (23.62 ± 3.74). All asthmatic patients were considered to have a low type- 2 asthma phenotype according to blood eosinophils counts, FeNO and IgE levels criteria. Peripheral blood CD4+ T cells were isolated, mRNA sequencing was conducted. Moreover, plasma was also taken from the same blood samples of the same previous individuals, EVs were isolated, EVs RNA was extracted and small/microRNA-Seq was performed.
The transcriptomic profiles of delayed processed CD4+ T cells showed only 3 differentially expressed genes at FDR < 0.1 when comparing atopic with healthy individuals. CD4+ T cells of healthy donors were not harshly affected by the delayed ex vivo blood incubation, while a drastic change has been shown in CD4+ T cells of atopic patients following the delayed blood processing accompanying by downregulation atopy-related biological pathways such as IL-2 and IL-17 signaling pathways. Concordant results were observed on the epigenetic level through H3K27ac profiles. IFN signaling pathways dominated the CD4+ T cells responses solely in low type-2 obese asthmatics represented by upregulation of different ISGs such as IFITM3, IFIT3, OAS2, OAS3, EIF2AK2, MX1, USP18, GBP3 genes, which correlated positively with lung function parameters including FEV1, FVC, VC max, TIFF, IC and PEF and negatively with the airway inflammation marker; FeNO. Viral infection pathways were also enriched for low type-2 obese asthmatics augmented by upregulation of different toll-like receptor genes such as TLR1, TLR-2, TLR-3, TLR-4, TLR-6, and TLR-8. Furthermore, obesity gene markers like IL15 and SOCS3 were also up-regulated in CD4+ T cells from obese asthmatics compared to both non-obese asthmatics and healthy controls. On the other hand, gap junction and GPCR ligand binding pathways were enriched in both low type-2 asthma groups. EVs miRNA clusters such as miR- 2329 and miR-106b seemed to be assigned to IFN signaling and viral infection pathways, respectively, in low type-2 obese asthmatics. In addition, single Plasma EV downregulated miRNAs including miR-665, miR-4419b, miR-4769-3p, miR-6893-5p, miR-4743-3p, miR-6721-5p, miR-1207-5p, miR-6132, miR-4700-3p, miR-4731-5p, miR-5089-5p, miR-502-5p, miR-6088, miR-148a-5p and miR-373-3p seemed to target most of the enriched ISGs of IFN signaling pathway in CD4+ T cells.
In conclusion, the dominance of the IFN signaling pathways and their association with viral infection pathways in CD4+ T cells response could underpin the underlying molecular mechanism of low type-2 obesity-associated asthma. The IFN signaling pathway enriched ISGs, their associated miRNAs and other miRNA clusters might be a target for biological and stratified therapies for this unique asthma phenotype. |
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| Umfang: | 116 Seiten |
| DOI: | 10.17192/z2022.0005 |