title: MiR-146a negatively regulates TLR2-induced inflammatory responses in keratinocytes.
abstract: Keratinocytes represent the first line of defense against pathogens in the skin and have important roles in initiating and regulating inflammation during infection and autoimmunity. Here we investigated the role of miR-146a in the regulation of the innate immune response of keratinocytes. Toll-like receptor 2 (TLR2) stimulation of primary human keratinocytes resulted in an NF-κB- and mitogen-activated protein kinase-dependent upregulation of miR-146a expression, which was surprisingly long lasting, contrasting with the rapid and transient induction of inflammatory mediators. Overexpression of miR-146a significantly suppressed the production of IL-8, CCL20, and tumor necrosis factor-α, which functionally suppressed the chemotactic attraction of neutrophils by keratinocytes. Inhibition of endogenous miR-146a induced the production of inflammatory mediators even in nonstimulated keratinocytes, and potentiated the effect of TLR2 stimulation. Transcriptomic profiling revealed that miR-146a suppresses the expression of a large number of immune-related genes in keratinocytes. MiR-146a downregulated interleukin-1 receptor-associated kinase 1 and TNF receptor-associated factor 6, two key adapter molecules downstream of TLR signaling, and suppressed NF-κB promoter-binding activity as shown by promoter luciferase experiments. Together, these data identify miR-146a as a regulatory element in keratinocyte innate immunity, which prevents the production of inflammatory mediators under homeostatic conditions and serves as a potent negative feedback regulator after TLR2 stimulation.
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Florian
authors.initials: F
authors.lastname: Meisgen
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu Landén
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Dermatology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Aoxue
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bence
authors.initials: B
authors.lastname: Réthi
authors.affiliation: L'Oreal Research and Innovation, Clichy, France.
authors.forename: Charbel
authors.initials: C
authors.lastname: Bouez
authors.affiliation: L'Oreal Research and Innovation, Clichy, France.
authors.forename: Michela
authors.initials: M
authors.lastname: Zuccolo
authors.affiliation: L'Oreal Research and Innovation, Clichy, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gueniche
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mona
authors.initials: M
authors.lastname: Ståhle
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Enikö
authors.initials: E
authors.lastname: Sonkoly
authors.affiliation: L'Oreal Research and Innovation, Clichy, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Breton
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: andor.pivarcsi@ki.se.
authors.forename: Andor
authors.initials: A
authors.lastname: Pivarcsi
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002633:Chemotaxis / Q000276:immunology; D003872:Dermatitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D025461:Feedback, Physiological; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D035683:MicroRNAs / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D015054:Zymosan / Q000276:immunology / Q000378:metabolism
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D015054:Zymosan