Identifikace a charakterizace nových mechanismů regulujících bazální a pohotovostní granulopoezu

Daněk, Petr

ABSTRACT Neutrophils are essential cells of the immune system. They engage in pathogen clearance, inflammatory response, and wound healing. Proper production and activation of neutrophils is critical for the health of an individual, since several disorders are related to neutrophilic alterations. In this thesis, we explore three previously uncharacterized mechanisms that might be involved in the regulation of neutrophilic differentiation. First, we addressed the role of the canonical Wnt signaling pathway. This signaling is executed by interaction of -catenin with TCF/LEF transcription factors. We employed a murine model that specifically inactivates -catenin-TCF/LEF-mediated transcription by expressing a dominant negative form of TCF4 (dnTCF4). Using this model in combination with several in vitro and in vivo assays we demonstrated that -catenin-TCF/LEF signaling directly upregulates expression of G-CSF receptor in hematopoietic progenitors, imposing myeloid commitment and favoring neutrophilic differentiation. This appeared to be especially important during the response to systemic infection, termed emergency granulopoiesis, as dnTCF4-expressing mice showed high susceptibility to Candida albicans infection. Remarkably, the critical role of -catenin-TCF/LEF signaling for neutrophil differentiation...

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