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.

The Urokinase Receptor-Derived Peptide UPARANT Mitigates Angiogenesis in a Mouse Model of Laser-Induced Choroidal Neovascularization

“…17 Formyl peptide receptors belong to a family of transmembrane G protein-coupled receptors that regulate the production of angiogenic and inflammatory factors through the modulation of transcription factors including hypoxia-inducible factor (HIF)-1, signal transducer and activator of transcription factor 3 (STAT3), nuclear factor kB (NF-kB), and cAMP response element binding protein (CREB). [18][19][20] Among peptide inhibitors of uPAR, the tetrapeptide Ac-L-Arg-Aib-L-Arg-L-Ca(Me)Phe-NH 2 , named UPARANT, displays lasting resistance to enzymatic digestion and high stability in blood and plasma; it strongly inhibits endothelial cell migration and proliferation by interfering with the complex cross talk between uPAR and FPRs. 21 In vitro, UPARANT reduces capillary sprout formation, whereas in vivo, it inhibits VEGFinduced vascularization in a rabbit corneal pocket assay and recovers retinal neovascularization, inner BRB leakage, and visual dysfunction in a mouse model of oxygen-induced retinopathy (OIR).…”

Staphylococcus aureus Esx Factors Control Human Dendritic Cell Functions Conditioning Th1/Th17 Response

“…We also investigated the mechanisms underlying the cytokine production by studying kinetics of activation of MAPK p38 and NF-kB p65 pathways (Figure 5), known regulators of S. aureus -induced immune response (Krishna and Miller, 2012; Armbruster et al, 2016). We observed that wt USA300 and esx mutants stimulate intracellular MAPK and NF-kB activation with different kinetics and to a different extent.…”

Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFκB2 (p100)

“…The MAP kinases, such as p38, have been reported to act as upstream kinases mediating CREB phosphorylation at Ser133 [29, 30]. We, therefore, investigated the effect of p100 on MAPK and their upstream kinase activation.…”