miR-146b probably assists miRNA-146a in the suppression of keratinocyte proliferation and inflammatory responses in psoriasis

Helen Hermann, Toomas Runnel, Alar Aab, Hansjörg Baurecht, Elke Rodriguez, Nathaniel Magilnick, Egon Urgard, Liisi Šahmatova, Ele Prans, Julia Maslovskaja, Kristi Abram, Maire Karelson, Bret Kaldvee, Paula Reemann, Uku Haljasorg, Beate Rückert, Paulina Wawrzyniak, Michael Weichenthal, Ulrich Mrowietz, Andre FrankeChristian Gieger, Jonathan Barker, Richard Trembath, Lam C. Tsoi, James T. Elder, Eric R. Tkaczyk, Kai Kisand, Pärt Peterson, Külli Kingo, Mark Boldin, Stephan Weidinger, Cezmi A. Akdis, Ana Rebane

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Abstract

 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 the present study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in lesional skin of psoriasis patients. The expression of miR-146a was about 2-fold higher than that of miR-146b in healthy human skin and it was more strongly induced by stimulation of pro-inflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of psoriasis patients, among which FERMT1 was verified as 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 miR-146a 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 to 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.
Original languageEnglish
JournalJournal of Investigative Dermatology
Early online date6 Jun 2017
DOIs
Publication statusE-pub ahead of print - 6 Jun 2017

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