Moelculare mechanisms and functional consequences of viral TLR3 ligand signalling in mesenchymal stromal cells of the nasal mucosa
Final Report Abstract
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.
Publications
- Stimulation of mesenchymal stromal cells (MSCs) via TLR3 reveals a novel mechanism of autocrine priming. FASEB J. 2014 Sep;28(9):3856-66
Dumitru CA, Hemeda H, Jakob M, Lang S, Brandau S
(See online at https://doi.org/10.1096/fj.14-250159) - Orbital Fibroblasts From Graves' Orbitopathy Patients Share Functional and Immunophenotypic Properties With Mesenchymal Stem/Stromal Cells. Invest Ophthalmol Vis Sci. 2015 Oct;56(11):6549-57
Brandau S, Bruderek K, Hestermann K, Görtz GE, Horstmann M, Mattheis S, Lang S, Eckstein A, Berchner- Pfannschmidt U
(See online at https://doi.org/10.1167/iovs.15-16610) - Adenosine metabolism of human mesenchymal stromal cells isolated from patients with head and neck squamous cell carcinoma. Immunobiology. 2016 Jan 30
Schuler PJ, Westerkamp AM, Kansy BA, Bruderek K, Dissmann PA, Dumitru CA, Lang S, Jackson EK, Brandau S
(See online at https://doi.org/10.1016/j.imbio.2016.01.013)
