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microRNAs in Psoriasis

      Psoriasis is a chronic inflammatory skin condition resulting from a complex interplay among the immune system, keratinocytes, susceptibility genes, and environmental factors. However, the pathogenesis of psoriasis is not completely elucidated. microRNAs represent a promising class of small, noncoding RNA molecules that function to regulate gene expression. Although microRNA research in psoriasis and dermatology is still relatively new, evidence is rapidly accumulating for the role of microRNAs in the pathogenesis of psoriasis and other chronic inflammatory conditions. In this article, we present a comprehensive review of what is known about microRNAs and their role in the pathogenesis of psoriasis.

      Abbreviations:

      IRAK1 (interleukin-1 receptor-associated kinase 1), miRNA (microRNA), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), PBMCs (peripheral blood mononuclear cells), pre-miRNA (precursor miRNA), pri-miRNA (primary miRNA), TNF-α (tumor necrosis factor-α)

      Introduction

      Psoriasis is a chronic immunoinflammatory skin condition that affects approximately 2% of the Caucasian population (
      • Kurd S.K.
      • Gelfand J.M.
      The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004.
      ). The pathogenesis of psoriasis is the result of a complex interplay between the immune system, keratinocytes, genes, and environmental factors. Dendritic cells (
      • Glitzner E.
      • Korosec A.
      • Brunner P.M.
      • et al.
      Specific roles for dendritic cell subsets during initiation and progression of psoriasis.
      ), antimicrobial peptides (
      • Lande R.
      • Botti E.
      • Jandus C.
      • et al.
      The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis.
      ), and the T helper (Th-1, Th-17) cell population (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • et al.
      Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
      ,
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ) with their respective cytokines (e.g., IFN-γ, IL-17, IL-22, IL-23) (
      • Johansen C.
      • Usher P.A.
      • Kjellerup R.B.
      • et al.
      Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.
      ,
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • et al.
      Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
      ,
      • Langrish C.L.
      • Chen Y.
      • Blumenschein W.M.
      • et al.
      IL-23 drives a pathogenic T cell population that induces autoimmune inflammation.
      ,
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ,
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ) have all been shown to be essential to the pathogenesis of psoriasis. However, significant research gaps still exist.
      microRNAs (miRNAs) represent an abundant class of small, evolutionarily conserved, noncoding RNA molecules that posttranscriptionally regulate gene expression. These noncoding RNAs are fundamental to human life and disease states (
      • Esteller M.
      Non-coding RNAs in human disease.
      ). Evidence is rapidly accumulating for the role of miRNAs in the pathogenesis of inflammatory skin disorders. However, miRNA research in dermatology and psoriasis is still relatively new. Here, we present a comprehensive review of the developments, implications, and future directions of miRNA research on the study of psoriasis pathogenesis.

      Origin of miRNAs

      First discovered in Caenorhabditis elegans, miRNAs are small (approximately 22 nucleotides) noncoding RNAs derived from larger primary RNA transcripts in the human genome (
      • Lee R.C.
      • Feinbaum R.L.
      • Ambros V.
      The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.
      ). Individual miRNA genes are transcribed by polymerase II or III into primary miRNA (pri-miRNA) transcripts (
      • Borchert G.M.
      • Lanier W.
      • Davidson B.L.
      RNA polymerase III transcribes human microRNAs.
      ,
      • Cai X.
      • Hagedorn C.H.
      • Cullen B.R.
      Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs.
      ,
      • Lee Y.
      • Kim M.
      • Han J.
      • et al.
      MicroRNA genes are transcribed by RNA polymerase II.
      ) and subsequently processed into a precursor miRNA (pre-miRNA) by Drosha (RNASEN) and DGCR8 (DiGeorge syndrome critical region 8) enzymes (Figure 1) (
      • Han J.
      • Lee Y.
      • Yeom K.H.
      • et al.
      The Drosha-DGCR8 complex in primary microRNA processing.
      ,
      • Landthaler M.
      • Yalcin A.
      • Tuschl T.
      The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis.
      ,
      • Lee Y.
      • Ahn C.
      • Han J.
      • et al.
      The nuclear RNase III Drosha initiates microRNA processing.
      ). After nuclear processing, a pre-miRNA is exported into the cytoplasm by XPO5 (Exportin 5) for final processing by Dicer and loading into the RNA-induced silencing complex (
      • Leuschner P.J.
      • Ameres S.L.
      • Kueng S.
      • et al.
      Cleavage of the siRNA passenger strand during RISC assembly in human cells.
      ,
      • Matranga C.
      • Tomari Y.
      • Shin C.
      • et al.
      Passenger-strand cleavage facilitates assembly of siRNA into AGO2-containing RNAi enzyme complexes.
      ). The loaded miRNA–RNA-induced silencing complex is then guided to the 3′ untranslated region of target mRNA genes where it binds and disrupts translation or triggers mRNA degradation (
      • Lee R.C.
      • Feinbaum R.L.
      • Ambros V.
      The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.
      ,
      • Yekta S.
      • Shih I.H.
      • Bartel D.P.
      MicroRNA-directed cleavage of HOXB8 mRNA.
      ).
      Figure 1
      Figure 1Model of miRNA biogenesis and posttranscriptional regulation of genes. miRNA genes are transcribed by either RNA polymerase II or RNA polymerase III into primary miRNA transcripts, known as pri-miRNA. The pri-miRNAs are then folded into hairpins, which serve as substrates for an RNase III enzyme, Drosha (RNASEN) and its partner DGCR8 (DiGeorge critical region 8). Drosha endonucleotically cleaves the long chain pri-miRNAs into ∼70-nucleotide pre-miRNA. The pre-miRNAs are then exported into the cytoplasm by XPO5 (Exportin 5). Once outside the nucleus, the loop of pre-miRNA is cleaved off by another RNase family enzyme known as Dicer, generating an ∼22-nucleotide miRNA duplex. One strand of this miRNA duplex is then loaded into the RNA-induced silencing complex (RISC). The loaded miRNA-RISC complex then interacts with the 3′ untranslated region (3′UTR) of target mRNA genes where it binds and disrupts translation or triggers mRNA degradation.
      Since their discovery, more than 2,500 miRNAs have been reported in public repositories and are thought to regulate more than one-third of all protein-coding genes (
      • Lewis B.P.
      • Burge C.B.
      • Bartel D.P.
      Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.
      ). This makes miRNAs one of the most abundant regulators of gene expression in humans. miRNAs have now been associated with a broad range of normal and disease processes, including chronic inflammatory skin diseases (
      • Esteller M.
      Non-coding RNAs in human disease.
      ,
      • O'Connell R.M.
      • Baltimore D.
      MicroRNAs and hematopoietic cell development.
      ,
      • O'Connell R.M.
      • Rao D.S.
      • Baltimore D.
      microRNA regulation of inflammatory responses.
      ).

      Aberrant miRNAs in Psoriasis

      The link between miRNAs and psoriasis was first described in 2007 (
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ). To date, more than 250 miRNAs have been reported as aberrantly expressed in psoriasis tissue, the majority of which are found in peripheral blood or involved psoriatic skin (Supplementary Table S1 online). Several studies have compared the miRNA profiles of uninvolved psoriatic skin versus normal healthy skin, but failed to identify reproducible differences between these tissues (
      • Joyce C.E.
      • Zhou X.
      • Xia J.
      • et al.
      Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome.
      ,
      • Lerman G.
      • Avivi C.
      • Mardoukh C.
      • et al.
      MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R.
      ,
      • Raaby L.
      • Langkilde A.
      • Kjellerup R.B.
      • et al.
      Changes in mRNA expression precede changes in microRNA expression in lesional psoriatic skin during treatment with adalimumab.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      ). In addition, only small subsets of these dysregulated miRNAs in psoriasis have confirmed mRNA targets with established biological functions in the skin (Table 1). Here, we review the miRNAs most strongly implicated in the immunopathogenesis of psoriasis.
      Table 1Aberrantly expressed miRNAs in psoriasis with established biological targets and functions in skin
      miRNATissue/cell typeExpressionTarget genesBiological functionReferences
      miR-21Human skin, human PBMCsIncreasedTIMP3, TPM1, PDCD4, PTEN, IL12A, RECK, RTN4, NFIBRegulation of keratinocyte proliferation, inflammation, T-cell apoptosis, and angiogenesis(
      • Ichihara A.
      • Jinnin M.
      • Yamane K.
      • et al.
      microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris.
      ,
      • Joyce C.E.
      • Zhou X.
      • Xia J.
      • et al.
      Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome.
      ,
      • Liu L.Z.
      • Li C.
      • Chen Q.
      • et al.
      MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1alpha expression.
      ,
      • Lovendorf M.B.
      • Zibert J.R.
      • Gyldenlove M.
      • et al.
      MicroRNA-223 and miR-143 are important systemic biomarkers for disease activity in psoriasis.
      ,
      • Lovendorf M.B.
      • Mitsui H.
      • Zibert J.R.
      • et al.
      Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
      ,
      • Meisgen F.
      • Xu N.
      • Wei T.
      • et al.
      MiR-21 is up-regulated in psoriasis and suppresses T cell apoptosis.
      ,
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      )
      miR-31Human skinIncreasedFIH-1, STK40Regulation of keratinocyte differentiation, NF-κB activity, angiogenesis, and leukocyte migration to the skin(
      • Joyce C.E.
      • Zhou X.
      • Xia J.
      • et al.
      Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome.
      ,
      • Peng H.
      • Kaplan N.
      • Hamanaka R.B.
      • et al.
      microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation.
      ,
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Xu N.
      • Meisgen F.
      • Butler L.M.
      • et al.
      MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      )
      miR-135bHuman skin, primary human keratinocytesIncreasedCOL4A3Regulation of keratinocyte differentiation and proliferation(
      • Choi H.R.
      • Nam K.M.
      • Park S.J.
      • et al.
      Suppression of miR135b increases the proliferative potential of normal human keratinocytes.
      ,
      • Joyce C.E.
      • Zhou X.
      • Xia J.
      • et al.
      Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome.
      )
      miR-136Human skin, primary human keratinocytesIncreasedPPP2R2ARegulation of TGF-β1-induced keratinocyte proliferation arrest(
      • Zhang D.
      • Wang J.
      • Wang Z.
      • et al.
      miR-136 modulates TGF-beta1-induced proliferation arrest by targeting PPP2R2A in keratinocytes [e-pub ahead of print].
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      )
      miR-138Human PBMCsIncreasedRUNX3Regulation of the Th-1/Th-2 balance in CD4+ T cells(
      • Fu D.
      • Yu W.
      • Li M.
      • et al.
      MicroRNA-138 regulates the balance of Th1/Th2 via targeting RUNX3 in psoriasis.
      )
      miR-146aHuman skin, human PBMCs, primary human keratinocytesIncreasedIRAK1, TRAF6, EGFRRegulation of hematopoietic development, inflammation, immune cell mediators, and keratinocyte proliferation(
      • Lovendorf M.B.
      • Mitsui H.
      • Zibert J.R.
      • et al.
      Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
      ,
      • Meisgen F.
      • Xu Landen N.
      • Wang A.
      • et al.
      MiR-146a negatively regulates TLR2-induced inflammatory responses in keratinocytes.
      ,
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Xia P.
      • Fang X.
      • Zhang Z.H.
      • et al.
      Dysregulation of miRNA146a versus IRAK1 induces IL-17 persistence in the psoriatic skin lesions.
      ,
      • Zhang W.
      • Yi X.
      • Guo S.
      • et al.
      A single-nucleotide polymorphism of miR-146a and psoriasis: an association and functional study.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      )
      miR-155Human skinIncreasedCTLA-4Regulation of hematopoietic development and inflammation(
      • Ichihara A.
      • Jinnin M.
      • Yamane K.
      • et al.
      microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris.
      ,
      • Lovendorf M.B.
      • Mitsui H.
      • Zibert J.R.
      • et al.
      Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
      )
      miR-184Human skinIncreasedAGO2Regulation of posttranscriptional modification of mRNA and miRNA biogenesis via the miRISC complex(
      • Roberts J.C.
      • Warren R.B.
      • Griffiths C.E.
      • et al.
      Expression of microRNA-184 in keratinocytes represses argonaute 2.
      )
      miR-203Human skin, primary human keratinocytesIncreasedSOCS-3, SOCS-6, p63, TNFα, IL8, IL24Regulation of inflammation, STAT3 signaling, and keratinocyte proliferation/differentiation(
      • Lerman G.
      • Avivi C.
      • Mardoukh C.
      • et al.
      MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R.
      ,
      • Primo M.N.
      • Bak R.O.
      • Schibler B.
      • et al.
      Regulation of pro-inflammatory cytokines TNFalpha and IL24 by microRNA-203 in primary keratinocytes.
      ,
      • Raaby L.
      • Langkilde A.
      • Kjellerup R.B.
      • et al.
      Changes in mRNA expression precede changes in microRNA expression in lesional psoriatic skin during treatment with adalimumab.
      ,
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Wei T.
      • Xu N.
      • Meisgen F.
      • et al.
      Interleukin-8 is regulated by miR-203 at the posttranscriptional level in primary human keratinocytes [e-pub ahead of print].
      ,
      • Yi R.
      • Poy M.N.
      • Stoffel M.
      • et al.
      A skin microRNA promotes differentiation by repressing ‘stemness’.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      )
      miR-210Human PBMCsIncreasedFOXP3Regulation of regulatory T cells and their cytokine production(
      • Zhao M.
      • Wang L.T.
      • Liang G.P.
      • et al.
      Up-regulation of microRNA-210 induces immune dysfunction via targeting FOXP3 in CD4(+) T cells of psoriasis vulgaris.
      )
      miR-221/222Human skinIncreasedTIMP3, c-KIT, p57Regulation of keratinocyte and immune cell proliferation(
      • Joyce C.E.
      • Zhou X.
      • Xia J.
      • et al.
      Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      )
      miR-424Human skinIncreasedMEK1, Cyclin E1Regulation of keratinocyte proliferation(
      • Ichihara A.
      • Jinnin M.
      • Yamane K.
      • et al.
      microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris.
      ,
      • Lerman G.
      • Avivi C.
      • Mardoukh C.
      • et al.
      MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R.
      )
      miR-99aHuman skinDecreasedIGF-1RRegulation of keratinocyte proliferation and differentiation(
      • Ichihara A.
      • Jinnin M.
      • Yamane K.
      • et al.
      microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris.
      ,
      • Lerman G.
      • Avivi C.
      • Mardoukh C.
      • et al.
      MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R.
      ,
      • Lovendorf M.B.
      • Mitsui H.
      • Zibert J.R.
      • et al.
      Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
      )
      miR-125bHuman skin, human serumDecreasedFGFR2, TNF-αRegulation of keratinocyte proliferation/differentiation and inflammation(
      • Koga Y.
      • Jinnin M.
      • Ichihara A.
      • et al.
      Analysis of expression pattern of serum microRNA levels in patients with psoriasis.
      ,
      • Lovendorf M.B.
      • Mitsui H.
      • Zibert J.R.
      • et al.
      Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
      ,
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Xu N.
      • Brodin P.
      • Wei T.
      • et al.
      MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2.
      )
      Abbreviations: NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells PBMCs, peripheral blood mononuclear cells; STAT3, signal transducer and activator of transcription 3; TGF-β1, transforming growth factor-β1.

      miR-203

      Multiple studies have reported miR-203 as being dysregulated in patients with psoriasis (
      • Lerman G.
      • Avivi C.
      • Mardoukh C.
      • et al.
      MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R.
      ,
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      ). The first skin-specific miRNA identified, miR-203, is made almost exclusively by keratinocytes and regulates cell differentiation in a protein kinase C–dependent manner (
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Sonkoly E.
      • Wei T.
      • Pavez Lorie E.
      • et al.
      Protein kinase C-dependent upregulation of miR-203 induces the differentiation of human keratinocytes.
      ). Increased miR-203 in psoriatic tissue strongly correlates with a decrease in suppressor of cytokine signaling 3 (SOCS3) and subsequent elevation in signal transducer and activator of transcription-3 (STAT3), a transcription factor in keratinocytes that is fundamental to the development of psoriatic skin lesions (
      • Sonkoly E.
      • Wei T.
      • Pavez Lorie E.
      • et al.
      Protein kinase C-dependent upregulation of miR-203 induces the differentiation of human keratinocytes.
      ). miR-203 may also dampen the pro-inflammatory response by direct targeting and repression of tumor necrosis factor-α (TNF-α), IL-8, and IL-24 mRNA (
      • Primo M.N.
      • Bak R.O.
      • Schibler B.
      • et al.
      Regulation of pro-inflammatory cytokines TNFalpha and IL24 by microRNA-203 in primary keratinocytes.
      ,
      • Wei T.
      • Xu N.
      • Meisgen F.
      • et al.
      Interleukin-8 is regulated by miR-203 at the posttranscriptional level in primary human keratinocytes [e-pub ahead of print].
      ). The importance of miR-203 on skin morphogenesis and keratinocyte differentiation was further corroborated by showing that its upregulation in suprabasal keratinocytes results in inhibition of p63, a key regulator of basal cell “stemness” (
      • Yi R.
      • Poy M.N.
      • Stoffel M.
      • et al.
      A skin microRNA promotes differentiation by repressing ‘stemness’.
      ).

      miR-146a

      One of the most highly upregulated miRNAs in psoriatic skin is miR-146a (
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Xia P.
      • Fang X.
      • Zhang Z.H.
      • et al.
      Dysregulation of miRNA146a versus IRAK1 induces IL-17 persistence in the psoriatic skin lesions.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      ). miR-146a is a crucial negative regulator of inflammation, autoimmunity, and the innate immune response (
      • O'Connell R.M.
      • Rao D.S.
      • Baltimore D.
      microRNA regulation of inflammatory responses.
      ,
      • Taganov K.D.
      • Boldin M.P.
      • Chang K.J.
      • et al.
      NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses.
      ). This miRNA promotes resolution of the immune response by negatively regulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent inflammatory signals via direct targeting of TNF receptor–associated factor 6 and IL-1 receptor–associated kinase 1 (IRAK1) (
      • Meisgen F.
      • Xu Landen N.
      • Wang A.
      • et al.
      MiR-146a negatively regulates TLR2-induced inflammatory responses in keratinocytes.
      ,
      • O'Connell R.M.
      • Rao D.S.
      • Baltimore D.
      microRNA regulation of inflammatory responses.
      ). TNF receptor–associated factor 6 and IRAK1 are key signaling mediators involved in the production of pro-inflammatory cytokines (e.g., IL-6 and TNF-α) after toll-like receptor and IL-1 receptor activation (
      • O'Connell R.M.
      • Rao D.S.
      • Baltimore D.
      microRNA regulation of inflammatory responses.
      ).
      Increased miR-146a is found in both the epidermal and dermal compartments of psoriatic skin, as well as the peripheral blood mononuclear cells (PBMCs) (
      • Lovendorf M.B.
      • Mitsui H.
      • Zibert J.R.
      • et al.
      Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
      ,
      • Xia P.
      • Fang X.
      • Zhang Z.H.
      • et al.
      Dysregulation of miRNA146a versus IRAK1 induces IL-17 persistence in the psoriatic skin lesions.
      ). High levels of miR-146a in the skin and PBMCs of patients with psoriasis have a strong positive correlation with IL-17, an increasingly important cytokine in the pathogenesis of psoriasis (
      • Xia P.
      • Fang X.
      • Zhang Z.H.
      • et al.
      Dysregulation of miRNA146a versus IRAK1 induces IL-17 persistence in the psoriatic skin lesions.
      ). Given the strong link between miR-146a, inflammation, and the immune responses, it is not surprising that this miRNA associates with pathogenic processes of psoriasis.

      miR-21

      miR-21, an important oncogene (i.e., oncomiR) that functions to promote inflammation and inhibit apoptosis, is also elevated in psoriatic skin (
      • Guinea-Viniegra J.
      • Jimenez M.
      • Schonthaler H.B.
      • et al.
      Targeting miR-21 to treat psoriasis.
      ,
      • Ichihara A.
      • Jinnin M.
      • Yamane K.
      • et al.
      microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris.
      ,
      • Joyce C.E.
      • Zhou X.
      • Xia J.
      • et al.
      Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome.
      ,
      • Lovendorf M.B.
      • Zibert J.R.
      • Gyldenlove M.
      • et al.
      MicroRNA-223 and miR-143 are important systemic biomarkers for disease activity in psoriasis.
      ,
      • Lovendorf M.B.
      • Mitsui H.
      • Zibert J.R.
      • et al.
      Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
      ,
      • Meisgen F.
      • Xu N.
      • Wei T.
      • et al.
      MiR-21 is up-regulated in psoriasis and suppresses T cell apoptosis.
      ,
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      ). Increased miR-21 has been localized to keratinocytes and infiltrating inflammatory cells (
      • Guinea-Viniegra J.
      • Jimenez M.
      • Schonthaler H.B.
      • et al.
      Targeting miR-21 to treat psoriasis.
      ,
      • Meisgen F.
      • Xu N.
      • Wei T.
      • et al.
      MiR-21 is up-regulated in psoriasis and suppresses T cell apoptosis.
      ). Further, it is upregulated in proliferative states due, in part, to the disruption of the degradation pathway of miR-21 (
      • Boele J.
      • Persson H.
      • Shin J.W.
      • et al.
      PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease.
      ). Elevated miR-21 in psoriatic skin correlates with enhanced TNF-α mRNA expression, and its inhibition in mice with psoriasis xenotransplants results in improved skin disease (
      • Guinea-Viniegra J.
      • Jimenez M.
      • Schonthaler H.B.
      • et al.
      Targeting miR-21 to treat psoriasis.
      ). Further, inhibition of miR-21 in activated primary CD4+ human T cells results in increased apoptosis suggesting that miR-21 in psoriatic skin may contribute to the persistence of infiltrating T-cell populations and chronic skin inflammation (
      • Meisgen F.
      • Xu N.
      • Wei T.
      • et al.
      MiR-21 is up-regulated in psoriasis and suppresses T cell apoptosis.
      ). These studies provide strong evidence for a role of miR-21 in the pathogenesis of psoriasis and its potential as a future therapeutic target.

      miR-184

      miR-184 has been shown to be upregulated in psoriatic skin (
      • Joyce C.E.
      • Zhou X.
      • Xia J.
      • et al.
      Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome.
      ) and may have a unique role in keratinocytes and keratinocyte-related diseases by directly affecting the expression of other miRNAs (
      • Roberts J.C.
      • Warren R.B.
      • Griffiths C.E.
      • et al.
      Expression of microRNA-184 in keratinocytes represses argonaute 2.
      ). miR-184 directly targets argonaute RNA-induced silencing complex catalytic component 2, a fundamental protein involved in the RNA-induced silencing complex, and, ultimately, miRNA biogenesis (
      • Roberts J.C.
      • Warren R.B.
      • Griffiths C.E.
      • et al.
      Expression of microRNA-184 in keratinocytes represses argonaute 2.
      ). miR-184 also inhibits miR-205 to maintain expression levels of keratinocyte SH2–containing phosphoinositide 5′-phosphatase 2, a regulator of Akt signaling and cell survival (
      • Yu J.
      • Ryan D.G.
      • Getsios S.
      • et al.
      MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia.
      ). However, the significance of this specific miRNA in psoriasis remains unclear because prior miRNA profiling studies did not find miR-184 to be significantly dysregulated in psoriatic skin.

      miR-210

      Upregulation of miR-210 in psoriasis has been reported (
      • Lerman G.
      • Avivi C.
      • Mardoukh C.
      • et al.
      MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R.
      ) and appears to contribute to inflammation by interfering with the immunosuppressive effects of regulatory T cells (
      • Zhao M.
      • Wang L.T.
      • Liang G.P.
      • et al.
      Up-regulation of microRNA-210 induces immune dysfunction via targeting FOXP3 in CD4(+) T cells of psoriasis vulgaris.
      ). miR-210 is increased in CD4+ T cells in patients with psoriasis and leads to increased pro-inflammatory cytokines (i.e., IFN-γ and IL-17) via direct targeting of FOXP3, a master regulator of the development of regulatory T cells (
      • Zhao M.
      • Wang L.T.
      • Liang G.P.
      • et al.
      Up-regulation of microRNA-210 induces immune dysfunction via targeting FOXP3 in CD4(+) T cells of psoriasis vulgaris.
      ). These findings provide support for regulatory T-cell dysfunction and miRNA-mediated regulation of this cell population in psoriasis. Additional studies are needed to further validate and establish the role of this miRNA in psoriatic disease.

      miR-221 and miR-222

      Increased levels of miR-221 and miR-222 have also been observed in psoriasis skin lesions (
      • Joyce C.E.
      • Zhou X.
      • Xia J.
      • et al.
      Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      ). Increased levels of these miRNAs correlate with a reduction in tissue inhibitor of metalloproteinase 3, a member of the matrix metalloprotease family (
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      ). Matrix metalloproteases are a group of enzymes involved in a broad range of cellular activities (e.g., cell proliferation, angiogenesis, and inflammation) and are altered in psoriasis tissues (
      • Fleischmajer R.
      • Kuroda K.
      • Hazan R.
      • et al.
      Basement membrane alterations in psoriasis are accompanied by epidermal overexpression of MMP-2 and its inhibitor TIMP-2.
      ). Therefore, increased miR-221 and miR-222 are thought to contribute to psoriasis by promoting epidermal proliferation via activated matrix metalloproteases (
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      ). Other psoriasis-associated miRNAs (e.g., miR-21) also target tissue inhibitor of metalloproteinase 3 (
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      ). These findings underscore the potential importance of tissue inhibitor of metalloproteinase 3 and matrix metalloproteases in the immunopathogenesis of psoriasis.

      miR-31

      miR-31 is upregulated in psoriatic skin (
      • Joyce C.E.
      • Zhou X.
      • Xia J.
      • et al.
      Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome.
      ,
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Xu N.
      • Meisgen F.
      • Butler L.M.
      • et al.
      MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
      ,
      • Yan S.
      • Xu Z.
      • Lou F.
      • et al.
      NF-kappaB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.
      ,
      • Zibert J.R.
      • Lovendorf M.B.
      • Litman T.
      • et al.
      MicroRNAs and potential target interactions in psoriasis.
      ) and directly inhibits serine/threonine kinase 40 (
      • Xu N.
      • Meisgen F.
      • Butler L.M.
      • et al.
      MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
      ) and protein phosphatase 6 (
      • Yan S.
      • Xu Z.
      • Lou F.
      • et al.
      NF-kappaB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.
      ). By direct targeting of serine/threonine kinase 40, miR-31 regulates NF-κB signaling and the leukocyte-attracting and endothelial cell–activating signals produced by keratinocytes (
      • Xu N.
      • Meisgen F.
      • Butler L.M.
      • et al.
      MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
      ). Similarly,
      • Yan S.
      • Xu Z.
      • Lou F.
      • et al.
      NF-kappaB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.
      showed that activation of NF-κB signaling results in the upregulation of miR-31 and subsequent enhanced keratinocyte proliferation through direct targeting of protein phosphatase 6. miR-31 is also induced by transforming growth factor-β1, a cytokine previously implicated in psoriasis (
      • Han G.
      • Williams C.A.
      • Salter K.
      • et al.
      A role for TGFbeta signaling in the pathogenesis of psoriasis.
      ,
      • Xu N.
      • Meisgen F.
      • Butler L.M.
      • et al.
      MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
      ). Of interest, miR-31 also has regulatory effects on vascular differentiation, keratinocyte migration during wound healing, and promotion of hair growth (anagen) by inhibition of the catagen and telogen stages of hair development (
      • Peng H.
      • Kaplan N.
      • Hamanaka R.B.
      • et al.
      microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation.
      ,
      • Xu N.
      • Meisgen F.
      • Butler L.M.
      • et al.
      MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
      ). These reports place miR-31 at the center of keratinocyte biology and skin development, supporting the notion that its dysregulation may directly contribute to the development of proliferating skin diseases, such as psoriasis.

      miR-125b

      In contrast to the upregulated miRNAs in psoriasis, miR-125b is decreased in the skin (
      • Lovendorf M.B.
      • Mitsui H.
      • Zibert J.R.
      • et al.
      Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
      ,
      • Sonkoly E.
      • Wei T.
      • Janson P.C.
      • et al.
      MicroRNAs: novel regulators involved in the pathogenesis of psoriasis?.
      ,
      • Xu N.
      • Brodin P.
      • Wei T.
      • et al.
      MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2.
      ) and serum of patients with psoriasis (
      • Koga Y.
      • Jinnin M.
      • Ichihara A.
      • et al.
      Analysis of expression pattern of serum microRNA levels in patients with psoriasis.
      ). Decreased expression of miR-125b in psoriasis skin compared with normal skin is primarily the result of decreased expression in keratinocytes (
      • Xu N.
      • Brodin P.
      • Wei T.
      • et al.
      MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2.
      ). This decrease in miR-125b results in increased proliferation and decreased differentiation of keratinocytes and is mediated through direct targeting of Fibroblast growth factor receptor 2 (FGFR2) (
      • Xu N.
      • Brodin P.
      • Wei T.
      • et al.
      MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2.
      ). In macrophages, decreased levels of miR-125b also correlate with increases in TNF-α, a direct target of miR-125b (
      • Tili E.
      • Michaille J.J.
      • Cimino A.
      • et al.
      Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock.
      ). Decreases in miR-125b may, therefore, directly contribute to psoriasis skin lesions via its regulation of keratinocyte proliferation and TNF-α signaling. The central role of TNF-α in psoriasis has already been established by the clinical efficacy of anti-TNF-α biologic therapies.

      miR-99a and miR-424

      miR-99a and miR-424 also play a role in the development of psoriatic skin. miR-99a is decreased in psoriatic skin (
      • Ichihara A.
      • Jinnin M.
      • Yamane K.
      • et al.
      microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris.
      ,
      • Lerman G.
      • Avivi C.
      • Mardoukh C.
      • et al.
      MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R.
      ,
      • Lovendorf M.B.
      • Mitsui H.
      • Zibert J.R.
      • et al.
      Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
      ) and reciprocally expressed in the epidermis with one of its direct targets, insulin-like growth factor-1R, a known promoter of keratinocyte proliferation and inhibitor of cell differentiation (
      • Lerman G.
      • Avivi C.
      • Mardoukh C.
      • et al.
      MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R.
      ). On the other hand, miR-424 is decreased in psoriatic skin and promotes abnormal keratinocyte proliferation by allowing for increases in the protein expression of MEK1 and cyclin E1, two key regulators of cell proliferation (
      • Ichihara A.
      • Jinnin M.
      • Yamane K.
      • et al.
      microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris.
      ). Together, these findings suggest that the function of miR-99a and miR-424 in normal skin may help maintain epidermal homeostasis by the direct inhibition of their respective mRNA targets. Although no other studies have validated the decreased levels of miR-424 in psoriatic skin, this miRNA can regulate TNF-α production (
      • Zhao H.
      • Wang J.
      • Gao L.
      • et al.
      MiRNA-424 protects against permanent focal cerebral ischemia injury in mice involving suppressing microglia activation.
      ) and has been shown to be increased in the hair shafts of patients with psoriasis (
      • Tsuru Y.
      • Jinnin M.
      • Ichihara A.
      • et al.
      miR-424 levels in hair shaft are increased in psoriatic patients.
      ).

      miRNAs and Psoriasis Susceptibility

      Genome-wide association studies have identified many psoriasis-associated genetic loci in the Caucasian population (
      • Nair R.P.
      • Henseler T.
      • Jenisch S.
      • et al.
      Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.
      ,
      • Russell T.J.
      • Schultes L.M.
      • Kuban D.J.
      Histocompatibility (HL-A) antigens associated with psoriasis.
      ,
      • Tiilikainen A.
      • Lassus A.
      • Karvonen J.
      • et al.
      Psoriasis and HLA-Cw6.
      ,
      • Tsoi L.C.
      • Spain S.L.
      • Knight J.
      • et al.
      Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.
      ). However, most genome-wide association study signals lie within noncoding regions of the human genome (
      • Maurano M.T.
      • Humbert R.
      • Rynes E.
      • et al.
      Systematic localization of common disease-associated variation in regulatory DNA.
      ). miRNAs and other noncoding RNAs make up more than 70% of noncoding RNA (
      • Venter J.C.
      • Adams M.D.
      • Myers E.W.
      • et al.
      The sequence of the human genome.
      ). Thus, it will be important to examine whether psoriasis-associated variants also disrupt or alter the expression of specific miRNAs and determine if they contribute to psoriasis susceptibility.
      In 2010, Chatzikyriakidou and colleagues studied the association between psoriatic arthritis risk in a cohort of patients with psoriasis from Greece and specific polymorphisms found in miR-146a (rs2910164) and one of its known targets, IRAK1 (rs3027898, rs1059703) (
      • Chatzikyriakidou A.
      • Voulgari P.V.
      • Georgiou I.
      • et al.
      The role of microRNA-146a (miR-146a) and its target IL-1R-associated kinase (IRAK1) in psoriatic arthritis susceptibility.
      ). There was no association between the rs2910164 miR-146a variant and psoriatic arthritis susceptibility, but a very strong association with the rs3027898 IRAK1 variant was observed (
      • Chatzikyriakidou A.
      • Voulgari P.V.
      • Georgiou I.
      • et al.
      The role of microRNA-146a (miR-146a) and its target IL-1R-associated kinase (IRAK1) in psoriatic arthritis susceptibility.
      ). Interestingly, the rs3027898 IRAK1 variant was also correlated with ankylosing spondylitis, suggesting a more general role for miR-146a and IRAK1 in inflammatory arthropathies (
      • Chatzikyriakidou A.
      • Voulgari P.V.
      • Georgiou I.
      • et al.
      The role of microRNA-146a (miR-146a) and its target IL-1R-associated kinase (IRAK1) in psoriatic arthritis susceptibility.
      ). In contrast, a separate study showed that the rs2910164 miR-146a allele was associated with increased psoriasis susceptibility in Han Chinese patients (
      • Zhang W.
      • Yi X.
      • Guo S.
      • et al.
      A single-nucleotide polymorphism of miR-146a and psoriasis: an association and functional study.
      ). Specifically, the rs2910164G allele resulted in reduced levels of miR-146a and impairment of its ability to regulate endothelial growth factor receptor, an important proliferative signal in keratinocytes and psoriasis skin (
      • Nanney L.B.
      • Stoscheck C.M.
      • Magid M.
      • et al.
      Altered [125I]epidermal growth factor binding and receptor distribution in psoriasis.
      ,
      • Zhang W.
      • Yi X.
      • Guo S.
      • et al.
      A single-nucleotide polymorphism of miR-146a and psoriasis: an association and functional study.
      ).
      miRNAs may also help explain the link between psoriasis risk and polymorphisms in BSG (basigin), a gene located within the psoriasis susceptibility locus 6 region (
      • Wu L.S.
      • Li F.F.
      • Sun L.D.
      • et al.
      A miRNA-492 binding-site polymorphism in BSG (basigin) confers risk to psoriasis in central south Chinese population.
      ). Carriers of the rs8259 BSG polymorphism have lower BSG mRNA expression levels in their PBMCs and a decreased psoriasis susceptibility risk (
      • Wu L.S.
      • Li F.F.
      • Sun L.D.
      • et al.
      A miRNA-492 binding-site polymorphism in BSG (basigin) confers risk to psoriasis in central south Chinese population.
      ). Notably, the rs8259 BSG polymorphism was localized to the 3′ untranslated region miR-492-dependent binding site and completely abolished miR-492 binding (
      • Wu L.S.
      • Li F.F.
      • Sun L.D.
      • et al.
      A miRNA-492 binding-site polymorphism in BSG (basigin) confers risk to psoriasis in central south Chinese population.
      ). Although their study did not find a significantly elevated level of miR-492 in the PBMCs of patients with psoriasis, it suggests that the link between this gene variant and psoriasis susceptibility could be due to the disruption of miRNA binding of the BSG gene, warranting further investigation.
      Finally, one report demonstrates the interplay between miR-148a and cell surface expression of HLA-C (
      • Kulkarni S.
      • Qi Y.
      • O'HUigin C.
      • et al.
      Genetic interplay between HLA-C and MIR148A in HIV control and Crohn disease.
      ), one of the strongest psoriasis susceptibility loci discovered to date (
      • Bergboer J.G.
      • Zeeuwen P.L.
      • Schalkwijk J.
      Genetics of psoriasis: evidence for epistatic interaction between skin barrier abnormalities and immune deviation.
      ). miR-148a binding with HLA-C mRNA directly affects cell surface expression of HLA-C and influences HIV control and Crohn’s disease susceptibility (
      • Kulkarni S.
      • Qi Y.
      • O'HUigin C.
      • et al.
      Genetic interplay between HLA-C and MIR148A in HIV control and Crohn disease.
      ). Although these findings do not establish a direct role for miR-148a in psoriasis, they do provide a mechanism whereby miRNAs interact with psoriasis susceptibility loci to ultimately impact disease phenotype. In this way, polymorphisms in specific miRNAs and/or their interaction with susceptibility genes may provide insights into the issue of “missing heritability” in complex, multigenic, chronic inflammatory diseases.

      miRNAs as Potential Biomarkers of Disease

      Multiple studies provide evidence supporting the utility of miRNAs as biomarkers of skin disease (
      • Jinnin M.
      Various applications of microRNAs in skin diseases.
      ). An area of considerable interest is whether a single miRNA or group of miRNAs can serve as biomarkers of psoriatic disease. To date, more than 100 miRNAs are reproducibly detected and abundant in the serum of patients with plaque psoriasis (
      • Pivarcsi A.
      • Meisgen F.
      • Xu N.
      • et al.
      Changes in the level of serum microRNAs in patients with psoriasis after antitumour necrosis factor-alpha therapy.
      ). Specific miRNAs (i.e., miR-19a and miR-424) have also been isolated from more easily accessible tissue such as the hair of patients with psoriasis (
      • Hirao H.
      • Jinnin M.
      • Ichihara A.
      • et al.
      Detection of hair root miR-19a as a novel diagnostic marker for psoriasis.
      ,
      • Tsuru Y.
      • Jinnin M.
      • Ichihara A.
      • et al.
      miR-424 levels in hair shaft are increased in psoriatic patients.
      ). Ready access to miRNAs as potential biomarkers of psoriasis represents an important field of discovery.
      Plasma miR-33 is increased in patients with psoriasis and positively correlates with insulin levels and calculated insulin resistance (
      • Garcia-Rodriguez S.
      • Arias-Santiago S.
      • Orgaz-Molina J.
      • et al.
      Abnormal levels of expression of plasma microRNA-33 in patients with psoriasis.
      ). A negative correlation between circulating levels of miR-126 and carotid intima-media thickness has also been described (
      • Garcia-Rodriguez S.
      • Arias-Santiago S.
      • Orgaz-Molina J.
      • et al.
      Abnormal levels of expression of plasma microRNA-33 in patients with psoriasis.
      ). Both of these findings are potentially important observations given the unclear mechanisms driving the increased risk of diabetes and cardiovascular disease in patients with psoriasis.
      The serum levels of miR-1266, a putative regulator of IL-17A, are also significantly increased in patients with plaque psoriasis and inversely correlated with psoriasis-involved body surface area and Psoriasis Area Severity Index (PASI) scores (
      • Ichihara A.
      • Jinnin M.
      • Oyama R.
      • et al.
      Increased serum levels of miR-1266 in patients with psoriasis vulgaris.
      ). High levels of miR-146a in psoriatic skin and PBMCs are also positively correlated with IL-17 levels and PASI scoring (
      • Xia P.
      • Fang X.
      • Zhang Z.H.
      • et al.
      Dysregulation of miRNA146a versus IRAK1 induces IL-17 persistence in the psoriatic skin lesions.
      ). Similarly, levels of miR-369-3p (
      • Guo S.
      • Zhang W.
      • Wei C.
      • et al.
      Serum and skin levels of miR-369-3p in patients with psoriasis and their correlation with disease severity.
      ), as well as miR-143 and miR-223 (
      • Lovendorf M.B.
      • Zibert J.R.
      • Gyldenlove M.
      • et al.
      MicroRNA-223 and miR-143 are important systemic biomarkers for disease activity in psoriasis.
      ), are upregulated in the serum and positively correlate with disease severity. However, there was no single miRNA identified in both studies that was elevated in the serum of patients with psoriasis.
      The ability to isolate miRNA from small skin samples or blood represents a potentially useful, noninvasive method of diagnosing and/or monitoring systemic inflammatory conditions. However, the lack of correlation between the various tissues studied suggests an incomplete understanding of the regulatory mechanisms of miRNA expression in skin, blood, and the hair (
      • Xia P.
      • Fang X.
      • Zhang Z.H.
      • et al.
      Dysregulation of miRNA146a versus IRAK1 induces IL-17 persistence in the psoriatic skin lesions.
      ). Until research generates a more thorough understanding of the role of miRNAs in psoriasis, discordant results should be expected and highlight the limitation of skin and serum association studies. Further, it adds emphasis to the need for standardized study designs, isolation techniques, miRNA expression profiling platform, and data analysis.

      Alteration of miRNA Profiles After Psoriasis Treatments

      The impact of systemic therapies on specific psoriasis–related miRNAs has also been explored. One report found that narrow-band ultraviolet B therapy results in epidermal decreases of miR-21 and increases in p53 and miR-125b (
      • Gu X.
      • Nylander E.
      • Coates P.J.
      • et al.
      Effect of narrow-band ultraviolet B phototherapy on p63 and microRNA (miR-21 and miR-125b) expression in psoriatic epidermis.
      ). The role of miRNAs in the phototherapy response is further supported by the observation that miR-4516 mediates downregulation of STAT3 and apoptosis in keratinocytes exposed to psoralen plus UVA therapy (
      • Chowdhari S.
      • Saini N.
      Hsa-miR-4516 mediated downregulation of STAT3/CDK6/UBE2N plays a role in PUVA induced apoptosis in keratinocytes.
      ).
      The alteration of miRNAs after treatment is not unique to phototherapy. miR-143 and miR-223 are significantly elevated in the PBMCs of patients with untreated psoriasis and subsequently decrease after methotrexate therapy (
      • Lovendorf M.B.
      • Zibert J.R.
      • Gyldenlove M.
      • et al.
      MicroRNA-223 and miR-143 are important systemic biomarkers for disease activity in psoriasis.
      ). Another report found that 38 miRNAs had increased in the serum after etanercept therapy (
      • Pivarcsi A.
      • Meisgen F.
      • Xu N.
      • et al.
      Changes in the level of serum microRNAs in patients with psoriasis after antitumour necrosis factor-alpha therapy.
      ). These posttreatment miRNA profile changes were observed in etanercept therapy responders, but were not observed in patients treated with methotrexate. In addition, the miRNA expression profile changes in the skin of patients with psoriasis treated with adalimumab were not seen at 4 days after the first injection, but changes were observed at 2 weeks (
      • Raaby L.
      • Langkilde A.
      • Kjellerup R.B.
      • et al.
      Changes in mRNA expression precede changes in microRNA expression in lesional psoriatic skin during treatment with adalimumab.
      ). Together, these findings suggest that the alteration of miRNA expression profiles after systemic psoriasis treatments is somewhat specific to each treatment, may be used as predictors of treatment efficacy, and can change at various time points during the treatment period.

      Challenges and Future Directions

      Although previous work suggests a functional role for miRNAs in the development of psoriasis, most studies to date involve small patient cohorts and are limited to association studies. Psoriasis-associated miRNAs need to be investigated further using comprehensive studies with in vitro and in vivo experiments designed to determine the molecular mechanisms and direct targets of specific miRNAs. A number of transgenic mouse models felt to closely resemble the phenotypic, histologic, and cytokine pathways of human psoriasis are available for such mechanistic studies (
      • Gudjonsson J.E.
      • Johnston A.
      • Dyson M.
      • et al.
      Mouse models of psoriasis.
      ,
      • van der Fits L.
      • Mourits S.
      • Voerman J.S.
      • et al.
      Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
      ). Recent psoriasis studies have begun to incorporate these mouse models into their miRNA profiling and screening studies (
      • Guinea-Viniegra J.
      • Jimenez M.
      • Schonthaler H.B.
      • et al.
      Targeting miR-21 to treat psoriasis.
      ,
      • Lerman G.
      • Avivi C.
      • Mardoukh C.
      • et al.
      MiRNA expression in psoriatic skin: reciprocal regulation of hsa-miR-99a and IGF-1R.
      ,
      • Raaby L.
      • Langkilde A.
      • Kjellerup R.B.
      • et al.
      Changes in mRNA expression precede changes in microRNA expression in lesional psoriatic skin during treatment with adalimumab.
      ,
      • Yan S.
      • Xu Z.
      • Lou F.
      • et al.
      NF-kappaB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.
      ).
      Studying the role and function of specific miRNAs along with global expression patterns of specific phenotypes will provide the clues that will lead to an understanding of central pathways and/or genes perturbed in this chronic inflammatory disease. However, a major limitation to the current miRNA studies in psoriasis is that they are almost completely exclusive to psoriasis vulgaris. Little is known about the miRNA profiles of the various psoriasis subtypes, including guttate, pustular, erythrodermic, thin/thick plaques, inverse, and the arthritis variants. Initial miRNA profiling studies on these variants may offer insight into the pathophysiology of psoriasis subtypes. Moreover, individual psoriasis-specific miRNAs may become the focus of new topical and systemic therapy development efforts. The use of topical miRNA-targeted therapies, including the use of cell-penetrating peptides and nanoparticles, has been demonstrated in pachyonychia congenital (
      • Hickerson R.P.
      • Smith F.J.
      • Reeves R.E.
      • et al.
      Single-nucleotide-specific siRNA targeting in a dominant-negative skin model.
      ,
      • Leachman S.A.
      • Hickerson R.P.
      • Schwartz M.E.
      • et al.
      First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder.
      ,
      • Smith F.J.
      • Hickerson R.P.
      • Sayers J.M.
      • et al.
      Development of therapeutic siRNAs for pachyonychia congenita.
      ) and melasma (
      • Yi X.
      • Zhao G.
      • Zhang H.
      • et al.
      MITF-siRNA formulation is a safe and effective therapy for human melasma.
      ). Inhibition of specific miRNAs has also been shown to be effective in preclinical mouse models of psoriasis (
      • Guinea-Viniegra J.
      • Jimenez M.
      • Schonthaler H.B.
      • et al.
      Targeting miR-21 to treat psoriasis.
      ) and breast cancer (
      • Devulapally R.
      • Sekar N.M.
      • Sekar T.V.
      • et al.
      Polymer nanoparticles mediated codelivery of antimiR-10b and antimiR-21 for achieving triple negative breast cancer therapy.
      ). The potential benefit of miRNA-targeted therapies in humans has also been demonstrated by the development and use of Miravirsen, an antisense inhibitor of miR-122 for the treatment of hepatitis C infections (
      • Janssen H.L.
      • Reesink H.W.
      • Lawitz E.J.
      • et al.
      Treatment of HCV infection by targeting microRNA.
      ).
      The considerable impact of psoriasis on patients and the comorbidities associated with this condition highlight the importance of elucidating the molecular details of the immunopathogenesis of this inflammatory disorder. It is crucial that ongoing psoriasis studies evaluate novel mechanisms of epigenetic regulation of gene expression, including miRNA-mediated posttranscriptional gene silencing. As our understanding of psoriasis pathophysiology increases, we anticipate that miRNAs will emerge as prominent players in the development of this and other chronic inflammatory skin conditions.

      Conflict of Interest

      KCD reports personal fees from AbbVie, Amgen, Lilly, Pfizer, Bristol Myers Squibb, Janssen, XenoPort, Novartis, and Celgene. GGK reports personal fees from Abbott, Amgen, ApoPharma, Astellas, Boehringer, Bristol Myers Squibb, Celgene, Idera, Isis, Janssen, Lilly, L’Oreal, Novartis, Pfizer, Vascular Biologics Limited, and UCB, and institutional support from Abbott, Amgen, and Janssen.

      Acknowledgments

      JEH would like to acknowledge support received from the Dermatology Foundation Dermatologist Investigator Research Fellowship. We would also like to thank Emir Tursic for his help with Figure 1 and Drs Emma Guttman-Yassky and James G. Krueger for their input during this project.

      Supplementary Material

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