Understanding psoriasis: Role of miRNAs

Abstract

Psoriasis is a chronic, immune-mediated inflammatory skin disease, with a multifactorial etiology and important immunologic, genetic and environmental components. Psoriasis vulgaris represents its most common form, with a variable prevalence across the globe. Although its pathogenesis remains to be fully elucidated, a lack of balance in the epigenetic network has been shown to trigger certain elements of this disease, possibly altering its outcome. MicroRNAs are small non-coding RNA molecules involved in RNA-silencing and the post-transcriptional regulation of gene expression, which also appear to mediate the immune dysfunction in psoriasis. Although microRNA research is a new field in dermatology and psoriasis, there is rapidly accumulating evidence for its major contribution in the pathogenesis of chronic inflammatory conditions, including psoriasis and other dermatological disorders. Furthermore, circulating miRNAs identified in patients' blood samples have been identified as promising biomarkers of diagnosis, prognosis or treatment response. Extended investigations in this field are required, as until now, the exact involvement of miRNAs in psoriasis have remained to be entirely elucidated. This short review highlights a number of the roles of miRNAs found in different stages of psoriasis.

Keywords: immune system; keratinocytes; microRNA; psoriasis.

Figure 1.

miRNA biosynthesis. miRNA genes are transcribed by RNA polymerase II as pri-miRNAs, which are subsequently processed by Drosha, resulting in pre-miRNA. Pre-miRNAs are then transported by the exportin 5-Ran GTPase shuttle system into the cytoplasm where they are cleaved by another RNase family enzyme (Dicer), resulting in the miRNA/miRNA duplex. During this phase, Dicer interacts with AGO2 proteins generating the RISC. Immediately following this, one strand of the miRNA duplex is removed while the single stranded miRNA remains in the complex and interacts with the 3′ untranslated region of target mRNA genes, inducing posttranscriptional silencing and translational repression. miRNA, microRNA; pri-miRNA, primary RNA; pre-miRNA, miRNA precursor; DGCR8, DiGeorge syndrome critical region 8; AGO2, argonaute 2; RISC, RNA-induced silencing complex.

Figure 2.

miR-21. TGF-β binds to the receptors leading to SMAD-2 or SMAD-3 phosphorylation, followed by aggregation with SMAD-4. SMAD 3/4 appears to induce the transcriptional induction of the synthesis of pri-miR-21, genes which are subsequently processed by Drosha, resulting in pre-miR-21. Pre-miR-21 is then transported by the exportin 5-Ran GTPase shuttle system into the cytoplasm where it is cleaved by another RNase family enzyme (Dicer), resulting miRNA/miRNA duplex. During this phase, Dicer interacts with AGO2 proteins generating the RISC. Immediately following this, one strand of the miRNA duplex is removed while the single stranded miRNA remains in the complex and interacts with the 3′ untranslated region of target mRNA genes, inducing posttranscriptional silencing and repressing translation of the inhibitory SMAD-7, thereby eliminating the negative feedback mechanism of TGF-β signaling. miRNA/miR, microRNA; pri-miR, primary RNA; pre-miR, miRNA precursor; DGCR8, DiGeorge syndrome critical region 8; AGO2, argonaute 2; RISC, RNA-induced silencing complex; TGF-β, transforming growth factor-β; SMAD, mothers against decapentaplegic homolog 7.

Figure 3.

miR-31. TGF-β binds to the receptors leading to SMAD phosphorylation, followed by aggregation with SMAD-4, which induces the synthesis of pri-miR-31, which is subsequently processed by Drosha, resulting in pre-miR-31. Pre-miR-31 is then transported by the exportin 5-Ran GTPase shuttle system into the cytoplasm where it is cleaved by another RNase family enzyme (Dicer), resulting in the miRNA/miRNA duplex and, finally, mature miR-31. miR-31 negatively regulates NIK. NIK is involved in phosphorylating IKKα and therefore in controlling the NF-κB pathway. miRNA/miR, microRNA; pri-miR, primary RNA; pre-miR, miRNA precursor; DGCR8, DiGeorge syndrome critical region 8; TGF-β, transforming growth factor-β; SMAD, mothers against decapentaplegic homolog 7; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; NIK, NF-κB-inducing kinase; IKK, inhibitor of NF-κB subunit α.

Figure 4.

miR-146. Toll-like receptor ligands bind to their receptor increasing the production of pri-miR-146. miR-146 genes are transcribed by RNA polymerase II as pri-miR-146, which are subsequently processed by Drosha, resulting in pre-miR-146. The pre-miR-146 is then transported by the exportin 5-Ran GTPase shuttle system into the cytoplasm where it is cleaved by another RNase family enzyme (Dicer), resulting in the miRNA/miRNA duplex and in the final step, mature miR-146. miR-146 downregulates the expression of TRAF6 and IRAK1. The decreased expression of these modulators leads to decreased phosphorylation of the IKK complex and thereby decreased activation of the NF-κB pathway. miRNA/miR, microRNA; pri-miR, primary RNA; pre-miR, miRNA precursor; DGCR8, DiGeorge syndrome critical region 8; TRAF6, TNF receptor-associated factor 6; IRAK1, interleukin 1 receptor-associated kinase 1; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; IKK, inhibitor of NF-κB.

Figure 5.

miR-155. miR-155 genes are transcribed by RNA polymerase II as pri-miR-155, which are subsequently processed by Drosha, resulting in pre-miR-155. Pre-miR-155 is then transported by the exportin 5-Ran GTPase shuttle system into the cytoplasm where it is cleaved by another RNase family enzyme (Dicer), resulting in the miRNA/miRNA duplex and, finally, mature miR-155 that targets the 5′ inositol phosphatase SHIP1, which downregulates its expression and, in turn, promotes sustained activation of the PI3K pathway, consequently enhancing the production of IFN-γ. miRNA/miR, microRNA; pri-miR, primary RNA; pre-miR, miRNA precursor; DGCR8, DiGeorge syndrome critical region 8; SHIP1, SH-2 containing inositol polyphosphatase 1; PI3K, phosphoinositide 3-kinase; IFN-γ; interferon-γ.