The Role of RhoH in eosinophil development and function
Final Report Abstract
Eosinophils are granulocytic leukocytes that have been implicated in a variety of pathophysiological conditions such as allergies, asthma and gastrointestinal inflammatory disorders. Given the increasing incidence of such diseases and the often unsatisfactory treatment options available, it is of considerable importance to better understand factors governing eosinophil biology and function both under normal and inflammatory conditions. Eosinophils are short lived effector and regulatory cells and their levels are regulated by two main mechanisms, prolongation of their survival as well as controlling their de novo generation in the bone marrow. Both of these processes are enhanced by cytokines, mainly IL-5, IL-3 and GM-CSF, with IL-5 being the most specific for eosinophils. These cytokines act through receptors composed of a cytokine-specific alpha chain and a common beta chain. While a number of intracellular pathways controlling eosinophil lifespan have been determined, very little is known about pathways controlling eosinophil development and generation. The small atypical GTPase RhoH was found to be highly expressed in eosinophils and further upregulated in patients with hypereosinophilic syndrome (HES), a condition characterised by chronically elevated eosinophil levels and tissue damage with sometimes fatal outcome. Rho family GTPases have been implicated in the regulation of cell migration, proliferation and survival of haematopoietic stem cells. The aim of this project was to elucidate the role of RhoH in eosinophils. I found that RhoH was upregulated by IL-5 and that it regulated IL-5 receptor expression. Furthermore, it also negatively regulated eosinophil development and maturation, probably by altering the balance of transcription factors involved in this process. This is particularly relevant since very few negative regulators of eosinophil development have been identified, and inhibiting eosinophil development might be therapeutically attractive for the treatment of e.g. allergic diseases.
Publications
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(2013). "CD8+ T cells producing IL-3 and IL-5 in non-IgE- mediated eosinophilic diseases." Allergy Nov 11, (Epub ahead of print)
Stoeckle C and Simon HU
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Death associated kinase 2 positively regulated migration of neutrophils and eosinophils. J. Leuk. Biol. 2013 Nov 1 (Epub ahead of print)
Geering B, Stoeckle C, Rožman S, Oberson K, Benarafa C, Simon HU
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Living and dying for inflammation: neutrophils, eosinophils, basophils. Trends Immunol. 2013 Aug;34(8):398-409
Geering B & Stoeckle C, Conus S, Simon HU
