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 Franke; Christian 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

doi:10.1016/j.jid.2017.05.012

miR-146b Probably Assists miRNA-146a in the Suppression of Keratinocyte Proliferation and Inflammatory Responses in Psoriasis

J Invest Dermatol. 2017 Sep;137(9):1945-1954. doi: 10.1016/j.jid.2017.05.012. Epub 2017 Jun 6.

Authors

Helen Hermann¹, Toomas Runnel², Alar Aab¹, Hansjörg Baurecht³, Elke Rodriguez³, Nathaniel Magilnick⁴, Egon Urgard¹, Liisi Šahmatova⁵, Ele Prans⁶, Julia Maslovskaja¹, Kristi Abram⁷, Maire Karelson⁷, Bret Kaldvee⁵, Paula Reemann¹, Uku Haljasorg¹, Beate Rückert⁸, Paulina Wawrzyniak⁸, Michael Weichenthal³, Ulrich Mrowietz³, Andre Franke⁹, Christian Gieger¹⁰, Jonathan Barker¹¹, Richard Trembath¹², Lam C Tsoi¹³, James T Elder¹⁴, Eric R Tkaczyk¹⁵, Kai Kisand¹, Pärt Peterson¹, Külli Kingo⁵, Mark Boldin⁴, Stephan Weidinger³, Cezmi A Akdis⁸, Ana Rebane¹⁶

Affiliations

¹ Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
² Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Institute of Molecular and Cellular Biology, University of Tartu, Tartu, Estonia.
³ Department of Dermatology, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany.
⁴ Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope National Medical Center, Duarte, California, USA.
⁵ Department of Dermatology and Venereology, University of Tartu, Tartu, Estonia; Dermatology Clinic, Tartu University Hospital, Tartu, Estonia.
⁶ Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Department of Dermatology and Venereology, University of Tartu, Tartu, Estonia.
⁷ Dermatology Clinic, Tartu University Hospital, Tartu, Estonia.
⁸ Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.
⁹ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
¹⁰ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
¹¹ Division of Genetics and Molecular Medicine, King's College London, London, UK; St John's Institute of Dermatology, King's College London, London, UK.
¹² Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹³ Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.
¹⁴ Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
¹⁵ Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁶ Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia. Electronic address: ana.rebane@ut.ee.

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 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Case-Control Studies
Cell Proliferation / genetics*
Cells, Cultured
Dermatitis / genetics
Dermatitis / pathology
Disease Models, Animal
Gene Expression Regulation*
Humans
Keratinocytes / metabolism*
Mice
Mice, Inbred C57BL
MicroRNAs / genetics*
Psoriasis / genetics*
Psoriasis / pathology
Real-Time Polymerase Chain Reaction / methods

Substances

MicroRNAs
Mirn146 microRNA, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding