TLR2 activation underlying immune regulation at interfaces
Final Report Abstract
In this study, we have identified a pathway of immune regulation that operates in the skin. We mimicked intense cutaneous contact to bacteria in different in vivo mouse models by using living bacteria and lipopeptides. We investigated AD as a model for massive cutaneous immune sensing of Gram-positive bacteria in humans. We found that cutaneous infection with Staphylococcus aureus caused immune suppression. The exposure to TLR2-6 ligands was sufficient to cause an almost complete reduction of consecutive cutaneous recall responses. This skin exposure induced accumulation of MDSC, allowing MDSC recruitment to the skin, and suppression of T cellmediated recall responses. Signals through TLR2 on skin-resident cells, but not on recruited hematopoietic cells, as well as cutaneous IL-6 induction, were necessary and sufficient for the expansion of MDSCs and consecutive immune suppression. These data demonstrate that cutaneous recognition of TLR2-6 ligands orchestrates a unique pathway of cutaneous immune modulation mediated by MDSCs, indicating a yet unknown level of immune counter-regulation. In the course of this project it turned out that the number of lipoproteins in pathogenic S. aureus strains is significantly higher than in non-pathogenic species. Many of the 67 lipoproteins in the epidemic strain S. aureus USA300 are involved in nutrient transport by acting as a binding proteins ABC transporters. However, of almost 30 % of the lipoproteins we don’t know what they are doing. One class of lipoproteins represent the so called Lpl lipoproteins. They are encoded as tandem genes on a pathogenicity island and occur only in the S. aureus species. In the course of this project we found out that these Lpl lipoproteins not only contribute to immune stimulation, but they also significantly enhance the host cell invasion. The enhanced invasion in host cells is an elegant way to escape the immune detection (escape mechanism) and to be largely protected from antibiotic therapy. We assume that this one of the mechanisms why USA300 and related strains are so successful in spreading all over the world.
Publications
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Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells. Immunity 2014 Nov; 41(5):762-75
Skabytska Y, Wölbing F, Günther C, Köberle M, Kaesler S, Chen K, Guenova E, Demircioglu D, Kempf W, Volz T, Rammensee H, Röcken M, Götz F, Biedermann T
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Nonpathogenic bacteria alleviating ttopic dermatitis inflammation induce IL-10-producing dendritic cells and regulatory Tr1 cells. J Invest Dermatol. 2014; 134(1):96-104
Volz T, Skabytska Y, Guenova E, Chen KM, Frick J, Kirschning C, Kaesler S, Röcken M, Biedermann T
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Staphylococcus aureus skin colonization is promoted by barrier disruption and leads to local inflammation. Exp Dermatol. 2014; 22(2):153-5
Wanke I, Skabytska Y, Kraft B, Peschel A, Biedermann T, Schittek B
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Cutaneous bacteria induce immune suppression. Oncotarget. 2015 Oct 13; 6(31):30441-2
Skabytska Y, Biedermann T
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IL-4 abrogates Th17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells. Proc Natl Acad Sci USA. 2015 Feb;112(7):2163-8
Guenova E, Skabytska Y, Hoetzenecker W, Weindl G, Sauer K, Tham M, Kim K, Park J, Seo J, Levesque M, Volz T, Köberle M, Kaesler S, Thomas P, Mailhammer R, Ghoreschi K, Schäkel K, Amarov B, Eichner M, Schaller M, Röcken M, Biedermann T
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The νSaα Specific Lipoprotein Like Cluster (lpl) of S. aureus USA300 Contributes to Immune Stimulation and Invasion in Human Cells. PLoS Pathog 2015. 11: e1004984
Nguyen, M.T., B. Kraft, W. Yu, D.D. Demicrioglu, T. Hertlein, M. Burian, M. Schmaler, K. Boller, I. Bekeredjian-Ding, K. Ohlsen, B. Schittek & F. Götz
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Evaluation of Staphylococcus aureus Lipoproteins: Role in Nutritional Acquisition and Pathogenicity. Front Microbiol 2016 7: 1404
Shahmirzadi, S.V., M.T. Nguyen & F. Götz
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Staphylococcus aureus-derived lipoteichoic acid induces temporary T cell paralysis independent of Toll-like receptor 2. J Allergy Clin Immunol. 2016, Sep;138(3):780-790.e6
Kaesler S, Skabytska Y, Chen K, Kempf W, Volz T, Köberle M, Wölbing F, Hein U, Hartung T, Kirschning C, Röcken M, Biedermann T
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The role of innate immune signaling in the pathogenesis of atopic dermatitis and consequences for treatments. Semin Immunopathol. 2016 Jan; 38(1):29-43
Skabytska Y, Kaesler S, Volz T, Biedermann T
