Armbruster Nicole S, Richardson Jennifer R, Schreiner Jens, Klenk Juliane, Günter Manina, Autenrieth Stella E
Department of Internal Medicine II, University of Tübingen, Tübingen, Germany.
Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
Int J Med Microbiol. 2016 Dec;306(8):666-674. doi: 10.1016/j.ijmm.2016.09.002. Epub 2016 Sep 3.
Dendritic cells (DCs) are key players of the immune system and thus a target for immune evasion by pathogens. We recently showed that the virulence factor phenol-soluble modulin (PSM) produced by community-associated methicillin-resistant Staphylococcus aureus strains induces tolerogenic DCs upon Toll-like receptor (TLR) 2 activation via the p38-CREB-IL-10 pathway. Here, we addressed the question whether this tolerogenic phenotype of DCs induced by PSMs is specific for TLR2 activation. Therefore, bone marrow-derived DCs were treated with various ligands for extracellular and intracellular TLRs simultaneously with PSMα3. We show that PSMα3 modulates antigen uptake, maturation and cytokine production of DCs activated by TLR1/2, TLR2/6, TLR4, TLR7, and TLR9. Pre-incubation of DCs with a p38 MAP kinase inhibitor prevented the PSMα3-induced IL-10 secretion, as well as MHC class II up-regulation upon TLR activation. In consequence, the tolerogenic DCs induced by PSMα3 in response to several TLR ligands promoted priming of regulatory T cells. Thus, PSMs could be useful as inducers of tolerogenic DCs upon TLR ligand stimulation for therapeutic applications.
树突状细胞（DCs）是免疫系统的关键参与者，因此是病原体免疫逃逸的目标。我们最近发现，社区获得性耐甲氧西林金黄色葡萄球菌菌株产生的毒力因子酚溶性调节素（PSM）通过p38-CREB-IL-10途径在Toll样受体（TLR）2激活后诱导耐受性DCs。在这里，我们探讨了PSMs诱导的DCs这种耐受性表型是否对TLR2激活具有特异性的问题。因此，用各种细胞外和细胞内TLR配体同时处理骨髓来源的DCs和PSMα3。我们发现PSMα3可调节由TLR1/2、TLR2/6、TLR4、TLR7和TLR9激活的DCs的抗原摄取、成熟和细胞因子产生。用p38丝裂原活化蛋白激酶抑制剂预孵育DCs可阻止PSMα3诱导的IL-10分泌以及TLR激活后的MHC II类上调。因此，PSMα3响应几种TLR配体诱导的耐受性DCs促进了调节性T细胞的启动。因此，PSMs可作为TLR配体刺激后耐受性DCs的诱导剂用于治疗应用。
