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Projekt Druckansicht

Molekulare Mechanismen und funktionelle Konseqeuenzen einer Aktivierung von mesenchymalen Stromazellen der nasalen Mukosa durch virale TLR3 Liganden

Fachliche Zuordnung Hals-Nasen-Ohrenheilkunde, Phoniatrie und Audiologie
Förderung Förderung von 2012 bis 2017
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 202927002
 
Erstellungsjahr 2016

Zusammenfassung der Projektergebnisse

This project has elucidated key elements of the response of mesenchymal stromal cells of the nasal mucosa to TLR3-agonist-driven stimulation using Poly(I:C) as a model stimulus. We identified major signaling pathways involved, revealed a novel molecular mechanism of autocrine priming and explored the complex and timedependent interaction of stimulated MSC with NK cells. Molecular analyses demonstrated that NFκB and IRF3 undergo nuclear translocation after TLR3 activation, and that it is the p38 signaling pathway that mediates cytokine release. Furthermore we identified a distinct biphasic response consisting of an early inflammatory phase (IFN type I release) and late regulatory phase (IL-6 and IL-8 release). The early phase response triggered an autocrine amplification loop mediated by type I IFN that increased TLR3 expression and thus propagated the regulatory response enhancing the production of IL-6 and IL-8. In the second part of the project we took this biphasic response and investigated its effects on NK cells, a key innate immune cell that mediates anti-viral immunity and drives inflammation. Surprisingly the two responses had almost diametrically opposing effects; the inflammatory response from MSC supported NK classical effector functions known to promote anti-pathogen immunity. The regulatory response impaired NK effector functions and induced NK apoptosis, effectively terminating NK effector functions. Side projects to the major projects mentioned above identified tissue-resident MSC in the orbital fat of graves orbitopathy patients and delineated some cell biological differences to fibroblasts isolated from the same tissue. A study comparing the immunosuppressive capacity of tumor-derived MSC and MSC from nonmalignant control tissue showed that tumor MSC, due to reduced adenosine metabolism could possibly facilitate chronic inflammation in the tumor microenvironment. Collectively our data provide clear evidence for a role of MSC as non-hematopoietic immunoregulatory cells in infection and cancer. The interaction of stromal cells, such as MSC, and classical immune cells is likely to shape local tissue immune responses. This hypothesis should be further explored in future projects.

Projektbezogene Publikationen (Auswahl)

 
 

Zusatzinformationen

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