title: PSM Peptides of Staphylococcus aureus Activate the p38-CREB Pathway in Dendritic Cells, Thereby Modulating Cytokine Production and T Cell Priming.
abstract: The challenging human pathogen Staphylococcus aureus has highly efficient immune evasion strategies for causing a wide range of diseases, from skin and soft tissue to life-threatening infections. Phenol-soluble modulin (PSM) peptides are major pathogenicity factors of community-associated methicillin-resistant S. aureus strains. In previous work, we demonstrated that PSMs in combination with TLR2 ligand from S. aureus induce tolerogenic dendritic cells (DCs) characterized by the production of high amounts of IL-10, but no proinflammatory cytokines. This in turn promotes the activation of regulatory T cells while impairing Th1 response; however, the signaling pathways modulated by PSMs remain elusive. In this study, we analyzed the effects of PSMs on signaling pathway modulation downstream of TLR2. TLR2 stimulation in combination with PSMα3 led to increased and prolonged phosphorylation of NF-κB, ERK, p38, and CREB in mouse bone marrow-derived DCs compared with single TLR2 activation. Furthermore, inhibition of p38 and downstream MSK1 prevented IL-10 production, which in turn reduced the capacity of DCs to activate regulatory T cells. Interestingly, the modulation of the signaling pathways by PSMs was independent of the known receptor for PSMs, as shown by experiments with DCs lacking the formyl peptide receptor 2. Instead, PSMs penetrate the cell membrane most likely by transient pore formation. Moreover, colocalization of PSMs and p38 was observed near the plasma membrane in the cytosol, indicating a direct interaction. Thus, PSMs from S. aureus directly modulate the signaling pathway p38-CREB in DCs, thereby impairing cytokine production and in consequence T cell priming to increase the tolerance toward the pathogen.
authors.affiliation: Department of Internal Medicine II, University of Tübingen, 72076 Tübingen, Germany;
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Armbruster
authors.affiliation: Department of Internal Medicine II, University of Tübingen, 72076 Tübingen, Germany;
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Richardson
authors.affiliation: Institute for Cell Biology, University of Tübingen, 72076 Tübingen, Germany;
authors.forename: Jens
authors.initials: J
authors.lastname: Schreiner
authors.affiliation: Department of Internal Medicine II, University of Tübingen, 72076 Tübingen, Germany;
authors.forename: Juliane
authors.initials: J
authors.lastname: Klenk
authors.affiliation: Department of Internal Medicine II, University of Tübingen, 72076 Tübingen, Germany;
authors.forename: Manina
authors.initials: M
authors.lastname: Günter
authors.affiliation: Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany;
authors.forename: Dorothee
authors.initials: D
authors.lastname: Kretschmer
authors.affiliation: Department of Women's Health, Research Institute for Women's Health, University of Tübingen, 72076 Tübingen, Germany;
authors.forename: Simone
authors.initials: S
authors.lastname: Pöschel
authors.affiliation: Department of Women's Health, Research Institute for Women's Health, University of Tübingen, 72076 Tübingen, Germany; Department of Cell and Tissue Engineering, Fraunhofer Institute for Interfacial Engineering and Biotechnology, 70569 Stuttgart, Germany; Department of Cardiology, University of California Los Angeles, Los Angeles, CA 90095;
authors.forename: Katja
authors.initials: K
authors.lastname: Schenke-Layland
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany; and.
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.affiliation: Medical Research Council Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Clark
authors.affiliation: Department of Internal Medicine II, University of Tübingen, 72076 Tübingen, Germany; Stella.Autenrieth@med.uni-tuebingen.de.
authors.forename: Stella E
authors.initials: SE
authors.lastname: Autenrieth
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000276:immunology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D057131:Immune Evasion / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001427:Bacterial Toxins; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D010455:Peptides; C025971:staphylococcal delta toxin