Psoriasis is an autoimmune disease driven by a Th17 response linked to the antimicrobial peptide (AMP) LL-37 that has been connected to the induction and chronicity of psoriasis. We show that keratinocytes secrete various immune biomarkers with a direct link to psoriasis immunopathogenesis. Under pro-inflammatory microenvironmental conditions, LL-37 was found to regulate keratinocyte secretion of various immune biomarkers (eg C-X-C motif chemokine ligand (CXCL)8 and interleukin (IL)-1β) and alter extracellular signal-regulated kinase (ERK)1/2 signalling. However, during neutral conditions LL-37 induced a different pattern of keratinocyte immune biomarker secretion (eg vascular endothelial growth factor, CXCL8 and IL-6). Thus, an interesting pattern emerged regarding the immunomodulatory effects of LL-37 on keratinocytes; in general, expression of immune biomarkers that were upregulated in a Th1-like microenvironment was downregulated in the presence of LL-37. In contrast, LL-37 reinforced the Th17 response. In active psoriatic skin lesions, LL-37 expression was found to be significantly upregulated, which was also evident from the unique diffuse epidermic expression pattern not found in healthy skin. Finally, successful phototherapy of psoriasis patients converted this LL-37 inflammatory psoriatic skin pattern into a more localized basal layer expression as found in healthy controls. Thus, these findings demonstrate that LL-37 has a significant role in skin immune homeostasis and that its interplay with keratinocytes may have a more direct role in the immunopathogenesis of psoriasis than previously thought.

中文翻译：

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在模拟银屑病的微环境中，角质形成细胞分泌受 LL-37 调节的多种炎症和免疫生物标志物

银屑病是一种自身免疫性疾病，由与抗菌肽 (AMP) LL-37 相关的 Th17 反应驱动，后者与银屑病的诱发和慢性化有关。我们表明角质形成细胞分泌与银屑病免疫发病机制直接相关的各种免疫生物标志物。在促炎微环境条件下，发现 LL-37 可调节角质形成细胞分泌的各种免疫生物标志物（例如 CXC 基序趋化因子配体 (CXCL)8 和白细胞介素 (IL)-1β）并改变细胞外信号调节激酶 (ERK)1/ 2 信号。然而，在中性条件下，LL-37 诱导了不同模式的角质形成细胞免疫生物标志物分泌（例如血管内皮生长因子、CXCL8 和 IL-6）。因此，关于 LL-37 对角质形成细胞的免疫调节作用出现了一个有趣的模式。一般来说，在 LL-37 存在下，在 Th1 样微环境中上调的免疫生物标志物的表达被下调。相比之下，LL-37 加强了 Th17 反应。在活动性银屑病皮损中，发现 LL-37 表达显着上调，这从健康皮肤中未发现的独特弥漫性表皮表达模式也可以看出。最后，银屑病患者的成功光疗将这种 LL-37 炎症性银屑病皮肤模式转化为在健康对照中发现的更局部的基底层表达。因此，这些发现表明 LL-37 在皮肤免疫稳态中具有重要作用，并且它与角质形成细胞的相互作用可能在银屑病的免疫发病机制中具有比以前认为的更直接的作用。