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MicroRNA in the Pathogenesis of Allergic Inflammation

Lu, Thomas X.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1329935942

Abstract Details

2012, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Allergic inflammation affects hundreds of millions of people worldwide. The pathogenesis of allergic inflammation is an area under active investigation. However, the role of miRNAs, a novel class of small RNA molecules 19-25 base pairs long that regulates gene expression post-transcriptionally, had not been explored at the start of this thesis. Using asthma and eosinophilic esophagitis (EoE) as model diseases of allergic inflammation, we identified miRNA signatures from murine experimental asthma, human EoE esophageal biopsies and IL-13 stimulated human esophageal / human bronchial epithelial cells. Accordingly, we identified commonly regulated miRNAs such as miR-21 and miR-146 that were involved in multiple allergic responses as well as miRNAs that were directly regulated by IL-13 including miR-375. Focusing on one of the most up-regulated miRNA miR-21, we developed a series of findings demonstrating that it directly represses IL-12p35 expression. Notably, miR-21 had the highest expression in dendritic cells, and miR-21 deficient dendritic cells produced significantly more IL-12 in response to LPS stimulation. Furthermore, miR-21 deficient mice had reduced lung eosinophilia following induction of allergic inflammation, with a prominent up-regulation of IL-12/IFNγ related pathways in the lung. Bronchoalveolar lavage fluid (BALF) from allergen challenged miR-21 deficient mice had increased Th1 cytokine IFNγ and decreased Th2 cytokine IL-4 compared to wildtype littermates. Re-stimulation of CD4+ T helper cells from the mice showed similar results. Conversely, miR-21 deficiency significantly enhanced the Th1 associated cutaneous delayed-type hypersensitivity responses. In complementary experiments concerning the role of miRNAs in allergy related responses, we found up-regulation of both miR-21 and miR-223 in an ex vivo eosinophil differentiation model. Notably, miR-21 deficiency led to reduced eosinophil progenitor growth while miR-223 deficiency enhanced eosinophil growth. Finally, in a distinct set of experiments aimed to define the role of miRNAs in allergic responses induced directly by IL-13, we noted that IL-13 stimulation of lung and esophageal epithelial cells resulted in the modulation of several miRNAs, with down-regulation of miR-375 in both epithelial cell types. In addition, miR-375 was down-regulated in esophageal biopsies from EoE patients. Esophageal miR-375 levels correlated with esophageal eosinophil levels and esophageal mast cell specific gene CPA3. Modulation of miR-375 level was sufficient to regulate IL-13 mediated epithelial gene expression, especially in the immunoinflammatory pathways. Focusing on the potential utility of miRNAs as biomarkers for allergic disease, we identified up-regulation of multiple miRNAs, most notably miR-146a, miR-146b and miR-223 in the plasma samples from EoE patients that could serve as both non-invasive diagnostic markers and potential epigenetic regulators of EoE. Collectively, these results demonstrate a key role of miRNAs in regulating germane pathways involved in allergic inflammation including polarization of the adaptive immune system, regulation of eosinophil production and differentiation and regulation of IL-13 induced responses.
Marc Rothenberg, MD PhD (Committee Chair)
John Bissler, MD (Committee Member)
Gregory Grabowski, MD (Committee Member)
Stuart Handwerger, MD (Committee Member)
Bruce Aronow, PhD (Committee Member)
404 p.
Immunology
microRNA; Allergy; Asthma; Eosinophilic Esophagitis; Th1; Th2;

Recommended Citations

Citations

  • Lu, T. X. (2012). MicroRNA in the Pathogenesis of Allergic Inflammation [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1329935942

    APA Style (7th edition)

  • Lu, Thomas. MicroRNA in the Pathogenesis of Allergic Inflammation. 2012. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1329935942.

    MLA Style (8th edition)

  • Lu, Thomas. "MicroRNA in the Pathogenesis of Allergic Inflammation." Doctoral dissertation, University of Cincinnati, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1329935942

    Chicago Manual of Style (17th edition)

ucin1329935942
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© 2012, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.