Hermann Helen, Runnel Toomas, Aab Alar, Baurecht Hansjörg, Rodriguez Elke, Magilnick Nathaniel, Urgard Egon, Šahmatova Liisi, Prans Ele, Maslovskaja Julia, Abram Kristi, Karelson Maire, Kaldvee Bret, Reemann Paula, Haljasorg Uku, Rückert Beate, Wawrzyniak Paulina, Weichenthal Michael, Mrowietz Ulrich, Franke Andre, Gieger Christian, Barker Jonathan, Trembath Richard, Tsoi Lam C, Elder James T, Tkaczyk Eric R, Kisand Kai, Peterson Pärt, Kingo Külli, Boldin Mark, Weidinger Stephan, Akdis Cezmi A, Rebane Ana
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Institute of Molecular and Cellular Biology, University of Tartu, Tartu, Estonia.
J Invest Dermatol. 2017 Sep;137(9):1945-1954. doi: 10.1016/j.jid.2017.05.012. Epub 2017 Jun 6.
miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In this study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in the lesional skin of patients with psoriasis. The expression of miR-146a was approximately twofold higher than that of miR-146b in healthy human skin, and it was more strongly induced by stimulation of proinflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of patients with psoriasis, among which FERMT1 was verified as a direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in the miR-146a encoding gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis-related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a and skin fibroblasts from miR-146a and miR-146b mice stimulated with psoriasis-associated cytokines as compared with wild-type mice. Our results indicate that besides miR-146a, miR-146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin.
微小RNA-146a抑制人类角质形成细胞以及不同皮肤炎症小鼠模型中的炎症反应。目前对于微小RNA-146b在皮肤中的作用知之甚少。在本研究中，我们证实了银屑病患者皮损皮肤中微小RNA-146a和微小RNA-146b（微小RNA-146a/b）表达增加。在健康人皮肤中，微小RNA-146a的表达比微小RNA-146b高约两倍，并且在角质形成细胞和成纤维细胞中，促炎细胞因子刺激能更强烈地诱导其表达。调节炎症反应或增殖的微小RNA-146a/b靶基因在银屑病患者皮肤中发生改变，其中FERMT1被证实为微小RNA-146a的直接靶标。对超过4000例银屑病病例和超过8000例对照的全基因组数据进行的计算机分析证实，银屑病与微小RNA-146a编码基因中的遗传变异之间存在中度关联。转染微小RNA-146a/b可抑制角质形成细胞增殖，而抑制则增强其增殖以及银屑病相关靶基因的表达。与野生型小鼠相比，在用银屑病相关细胞因子刺激的微小RNA-146a小鼠的培养角质形成细胞以及微小RNA-146a和微小RNA-146b小鼠的皮肤成纤维细胞中，检测到微小RNA-146a/b影响基因的表达增强。我们的结果表明，除了微小RNA-146a外，微小RNA-146b也有表达，并且可能能够调节银屑病皮肤中的炎症反应和角质形成细胞增殖。
