Rusca, Nicole-Lily. MiR-146a: a key microRNA involved in regulating mast cell survival and T lymphocyte differentiation. 2013, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10591
Mice that lack the p50 subunit of NF-kB (p50KO) are unable to mount airway eosinophilic inflammation due to the inability to produce IL-4, IL-5 and IL-13, which play distinct roles in asthma pathogenesis, and to a defect in the polarization of Th2 lymphocytes. Since mast cells are master effector cells in allergic responses, we evaluated whether the asthma-resistant phenotype observed in p50KO mice could be partially due to a defect in mast cell development or function. While our data indicate that p50KO mast cells may only marginally contribute to the airway inflammation defect of p50KO mice through a slight impairment in cytokine production, p50KO mast cells showed a marked increase in their ability to survive in response to withdrawal of essential cytokines, which likely correlated with a strong increase in the percentage of mast cells that was observed in the tissues of p50KO animals. Such improved survival of mast cells lacking p50 was due to altered expression of several molecules involved in regulating cell survival and cell death, such as Bcl2, A1 and BAX. Importantly, we also found that miR-146a, a miRNA known to regulate NF-kB signalling, was not expressed in IgE- or LPS-stimulated p50KO mast cells, and that in the context of mast cell survival, miR-146a acted as a pro-apoptotic factor, identifying therefore a new molecular network that regulates mast cell survival in response to a variety of signals (Chapter 2).
Previous work from our lab also pointed toward a role for miR-146a in the differentiation and/or activation of murine CD4 T lymphocytes. We therefore continued investigating a possible role for this miRNA not only in regulating mast cell survival, but also in the differentiation and function of T cells. We found that miR-146a is expressed at high levels in the effector and effector-memory T cell compartment in both mouse and human, and we provide evidences that miR-146a may regulate T cell expansion upon activation and possibly also memory formation (Chapter 3). A review on the role of miR-146a in immunity and disease is provided in Chapter 4.
Overall our work demonstrates that miR-221 and miR-146a play a key role in regulating mast cell activation, function and survival, and that miR-146a also contributes to the extent of T lymphocyte activation. Finally, we provide novel insights on the role of miRNAs in regulating various functions of mast cells and T lymphocytes in the immune response, contributing to the groundwork for a further understanding of the molecular mechanisms that may lead to immune-related diseases such as asthma, allergy, altered inflammatory responses, and mastocytosis.
|Committee Members:||Monticelli, Silvia and Sallusto, Federica|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Infection Biology > Biochemistry (Pieters)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||166 p.|
|Last Modified:||30 Jun 2016 10:54|
|Deposited On:||09 Dec 2013 12:28|
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