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IL-17A Dissociates Inflammation from Fibrogenesis in Systemic Sclerosis.
Journal of Investigative Dermatology ( IF 6.5 ) Pub Date : 2019-07-03 , DOI: 10.1016/j.jid.2019.05.026
Aleksandra Maria Dufour 1 , Julia Borowczyk-Michalowska 2 , Montserrat Alvarez 1 , Marie-Elise Truchetet 3 , Ali Modarressi 4 , Nicolò Costantino Brembilla 2 , Carlo Chizzolini 1
Affiliation  

IL-17A is abundant in scleroderma but its role in fibrogenesis is controversial. We interrogated the role of IL-17A in extracellular matrix deposition and inflammation by investigating its effects on keratinocytes and fibroblasts cross-talk and in organotypic skin cultures. Keratinocyte-conditioned media of resting, IL-17A-, and/or transforming growth factor-β-primed primary keratinocytes were used to stimulate healthy donors and scleroderma fibroblasts. Alternatively, organotypic cultures of full human skin were challenged with these cytokines. Keratinocyte-conditioned media tilted the balance of col-I to matrix metalloproteinase-1 production by fibroblasts in favor of matrix metalloproteinase-1, significantly more so in healthy donors than in scleroderma, resulting in enhanced extracellular matrix turnover, further increased by IL-17A. In organotypic skin, transforming growth factor-β induced an extensive pro-fibrotic gene signature, including the enhanced expression of several collagen genes associated with Wnt signaling. IL-17A strongly promoted the expression of pro-inflammatory genes, with no direct effects on collagen genes, and attenuated Wnt signaling induced by transforming growth factor-β. In this model, at the protein level, IL-17A significantly decreased col-I production. Our data strongly support a pro-inflammatory and antifibrogenic activity of IL-17A in the context of keratinocyte-fibroblast interaction and in full skin. These data help in directing and interpreting targeted therapeutic approaches in scleroderma.

中文翻译:

IL-17A使炎症从全身性硬化症的纤维化中解脱出来。

IL-17A在硬皮病中含量丰富,但其在纤维生成中的作用尚有争议。我们调查了IL-17A对角质形成细胞和成纤维细胞串扰以及器官型皮肤培养的影响,从而询问了IL-17A在细胞外基质沉积和炎症中的作用。静息的角质形成细胞条件培养基,IL-17A-和/或转化生长因子-β引发的原代角质形成细胞被用于刺激健康的供体和硬皮成纤维细胞。或者,用这些细胞因子攻击完整人类皮肤的器官型培养物。角质形成细胞条件培养基使成纤维细胞产生的col-I与基质金属蛋白酶-1的平衡向基质金属蛋白酶-1倾斜,在健康供体中比在硬皮病中明显更多,从而导致细胞外基质周转率提高,IL-17A进一步提高了细胞外基质周转率。在器官型皮肤中,转化生长因子-β诱导了广泛的促纤维化基因标记,包括与Wnt信号传导相关的几种胶原基因的增强表达。IL-17A强烈促进促炎基因的表达,对胶原基因没有直接影响,并且减弱了转化生长因子-β诱导的Wnt信号转导。在该模型中,在蛋白质水平上,IL-17A显着降低了col-1的产生。我们的数据强烈支持在角质形成细胞-成纤维细胞相互作用的情况下以及在整个皮肤中IL-17A的促炎和抗纤维化活性。这些数据有助于指导和解释硬皮病的靶向治疗方法。包括与Wnt信号转导相关的几种胶原基因的增强表达。IL-17A强烈促进促炎基因的表达,对胶原基因没有直接影响,并且减弱了转化生长因子-β诱导的Wnt信号转导。在该模型中,在蛋白质水平上,IL-17A显着降低了col-1的产生。我们的数据强烈支持在角质形成细胞-成纤维细胞相互作用的情况下以及在整个皮肤中IL-17A的促炎和抗纤维化活性。这些数据有助于指导和解释硬皮病的靶向治疗方法。包括与Wnt信号转导相关的几种胶原基因的表达增强。IL-17A强烈促进促炎基因的表达,对胶原基因没有直接影响,并且减弱了转化生长因子-β诱导的Wnt信号转导。在该模型中,在蛋白质水平上,IL-17A显着降低了col-1的产生。我们的数据强烈支持在角质形成细胞-成纤维细胞相互作用的情况下以及在整个皮肤中IL-17A的促炎和抗纤维化活性。这些数据有助于指导和解释硬皮病的靶向治疗方法。IL-17A显着降低了col-1的产生。我们的数据强烈支持在角质形成细胞-成纤维细胞相互作用的情况下以及在整个皮肤中IL-17A的促炎和抗纤维化活性。这些数据有助于指导和解释硬皮病的靶向治疗方法。IL-17A显着降低了col-1的产生。我们的数据强烈支持在角质形成细胞-成纤维细胞相互作用的情况下以及在整个皮肤中IL-17A的促炎和抗纤维化活性。这些数据有助于指导和解释硬皮病的靶向治疗方法。
更新日期:2019-12-19
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