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Immunomodulation by ectosomes

Eken, Ceylan. Immunomodulation by ectosomes. 2010, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_9288

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Abstract

Considerable progress has been made in recognizing microvesicles as important mediators of intercellular communication rather than irrelevant cell debris. Microvesicles released by budding directly from the cell membrane surface either spontaneously or in response to various stimuli are called ectosomes. Of particular interest is that ectosomes released by polymorphonuclear neutrophils (PMN-Ect) down regulate the inflammatory potential of macrophages. This finding was a real surprise since PMNs are known to be proinflammatory cells par excellence. Thus the very same cells known for their destruction capacity have the property of releasing ectosomes, which inhibit further macrophage activation, although various cytokines released by PMNs are chemotactic for macrophages. This might be a powerful regulatory mechanism responsible for the control of excess inflammation. In my thesis I wanted to
(1) see whether the same ectosomes have also the property to down regulate dendritic cells (DCs), so as to prevent the activation of the acquired immune system (T cells), when it is not required (section 1).
(2) see whether ectosomes from other cells would have similar properties. For this we investigated ectosomes released by erythrocytes (section 2).
(3) define the signaling pathways induced by ectosomes (section 3).
(1) PMN-Ect were recently shown to induce an anti-inflammatory response on human monocyte-derived macrophages (HMDMs). I found that PMN�Ect also inhibited the LPS-induced maturation of human monocyte-derived DCs (MoDCs). This effect was evidenced by reduced expression of cell surface markers (CD40, CD80, CD83, CD86 and HLA�DP DQ DR), inhibition of cytokine release (IL�8, IL�10, IL�12, and TNFα), and new morphological and functional characteristics (reduced phagocytic activity, and increased TGF-β1 release). Importantly, the skewed MoDC differentiation resulted in a reduced capacity to activate T-cells, suggesting an active role for PMN-Ect in adaptive immunity as well.
(2) Microvesicles derived from erythrocytes during storage had all the properties of ectosomes. E-ecto revealed an inhibitory potential on zymosan A and LPS activated HMDMs as shown by down-regulation of IL-8 and TNFα release. However, different from PMN-Ect, E-ecto did not enhance the release of TGF�β1. In addition, the effect of E�ecto was found to be long lasting. Thus, E-ecto transfused with erythrocytes may account for some of the immunosuppressive effects seen after blood transfusions
(3) The receptors and signaling pathways involved in ectosome-induced down-modulation are unknown. I showed that the encounter of PMN-Ect with HMDMs induced an immediate calcium flux. Mer receptor as well as the phosphatidylinositol 3�kinase (PI3K)/Akt pathway were activated, and NFκB translocation and phosphorylation were blocked. Consequently, the transcription of many proinflammatory genes in zymosan A activated HMDMs were reduced. Finally, my data revealed that TGF-β1 release induced by PMN-Ect was not related to a modification in its transcription.
Taken together these results suggest that ectosomes have a profound effect on the innate immune system, here macrophages, as well as on the induction of the adaptive immune system, here DCs, globally reprogramming these cells toward an immunosuppressive and possibly tolerogenic phenotype.
Advisors:Schifferli, Jürg A.
Committee Members:Hess, Christoph
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Ehemalige Einheiten Medizinische Fächer (Klinik) > Stationäre innere Medizin (Schifferli)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Ehemalige Einheiten Medizinische Fächer (Klinik) > Stationäre innere Medizin (Schifferli)
Item Type:Thesis
Thesis no:9288
Bibsysno:Link to catalogue
Number of Pages:138 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:21 Jan 2011 11:13

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