Synthetic antimicrobial and LPS-neutralising peptides suppress inflammatory and immune responses in skin cells and promote keratinocyte migration.
Synthetic antimicrobial and LPS-neutralising peptides suppress inflammatory and immune responses in skin cells and promote keratinocyte migration.
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DOI：
10.1038/srep31577
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发表时间：
2016-08-11
影响因子：
4.6
通讯作者：
Weindl G
中科院分区：
文献类型：
--
作者：
Pfalzgraff A;Heinbockel L;Su Q;Gutsmann T;Brandenburg K;Weindl G
新抗生素开发的停滞以及随之而来的耐药细菌的大量增加凸显了对新治疗选择的迫切需要。抗菌肽是治疗细菌感染的有前途的药物，最近的研究表明，Pep 19 -2.5，一种合成的抗脂多糖（LPS）肽（SALP），有效地中和革兰氏阴性（LPS）和革兰氏阳性（脂蛋白/肽，LP）细菌的致病因子，并防止败血症。在这里，我们研究了Pep 19 -2.5和结构上相关的化合物Pep 19 -4LF在细菌性皮肤感染中的治疗应用潜力。SALP抑制LP诱导的NF-κB p65和p38 MAPK磷酸化，并减少原代人角质形成细胞和真皮成纤维细胞中细胞因子的释放和基因表达。在LPS刺激的人单核细胞来源的树突状细胞和朗格汉斯样细胞中，肽阻断IL-6分泌，下调成熟标志物的表达并抑制树突状细胞迁移。两种SALP在所有研究的细胞类型中均显示出低细胞毒性。此外，SALP通过EGFR反式激活和ERK 1/2磷酸化显著促进细胞迁移，并加速角质形成细胞中的人工伤口闭合。嘌呤受体和金属蛋白酶介导肽诱导的角质形成细胞迁移。相反，SALP不影响角质形成细胞的增殖。总之，我们的数据表明了一种新的治疗急性和慢性皮肤感染患者的治疗靶点。
The stagnation in the development of new antibiotics and the concomitant high increase of resistant bacteria emphasize the urgent need for new therapeutic options. Antimicrobial peptides are promising agents for the treatment of bacterial infections and recent studies indicate that Pep19-2.5, a synthetic anti-lipopolysaccharide (LPS) peptide (SALP), efficiently neutralises pathogenicity factors of Gram-negative (LPS) and Gram-positive (lipoprotein/-peptide, LP) bacteria and protects against sepsis. Here, we investigated the potential of Pep19-2.5 and the structurally related compound Pep19-4LF for their therapeutic application in bacterial skin infections. SALPs inhibited LP-induced phosphorylation of NF-κB p65 and p38 MAPK and reduced cytokine release and gene expression in primary human keratinocytes and dermal fibroblasts. In LPS-stimulated human monocyte-derived dendritic cells and Langerhans-like cells, the peptides blocked IL-6 secretion, downregulated expression of maturation markers and inhibited dendritic cell migration. Both SALPs showed a low cytotoxicity in all investigated cell types. Furthermore, SALPs markedly promoted cell migration via EGFR transactivation and ERK1/2 phosphorylation and accelerated artificial wound closure in keratinocytes. Peptide-induced keratinocyte migration was mediated by purinergic receptors and metalloproteases. In contrast, SALPs did not affect proliferation of keratinocytes. Conclusively, our data suggest a novel therapeutic target for the treatment of patients with acute and chronic skin infections.