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Correspondence: Ryan M. O’Connell, Department of Pathology, University of Utah, 4280B EEJMRB, 15 North Medical Dr East, Salt Lake City, Utah 84112, USA.
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.
). The pathogenesis of psoriasis is the result of a complex interplay between the immune system, keratinocytes, genes, and environmental factors. Dendritic cells (
) 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 (
). 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 (
) and subsequently processed into a precursor miRNA (pre-miRNA) by Drosha (RNASEN) and DGCR8 (DiGeorge syndrome critical region 8) enzymes (Figure 1) (
). 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 (
). 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 (
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 (
). 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 (
). 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 (
). 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
miRNA
Tissue/cell type
Expression
Target genes
Biological function
References
miR-21
Human skin, human PBMCs
Increased
TIMP3, TPM1, PDCD4, PTEN, IL12A, RECK, RTN4, NFIB
Regulation of keratinocyte proliferation, inflammation, T-cell apoptosis, and angiogenesis
Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes 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 (
). 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 (
). 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” (
). 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) (
). 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 (
Increased miR-146a is found in both the epidermal and dermal compartments of psoriatic skin, as well as the peripheral blood mononuclear cells (PBMCs) (
Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
). 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 (
). 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 (
Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
). Increased levels of these miRNAs correlate with a reduction in tissue inhibitor of metalloproteinase 3, a member of the matrix metalloprotease family (
). 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 (
). Therefore, increased miR-221 and miR-222 are thought to contribute to psoriasis by promoting epidermal proliferation via activated matrix metalloproteases (
). These findings underscore the potential importance of tissue inhibitor of metalloproteinase 3 and matrix metalloproteases in the immunopathogenesis of psoriasis.
MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
). 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 (
MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
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 (
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 (
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 (
Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
). 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) (
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 (
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 (
). 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 (
). 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 (
). 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) (
). 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 (
). Interestingly, the rs3027898 IRAK1 variant was also correlated with ankylosing spondylitis, suggesting a more general role for miR-146a and IRAK1 in inflammatory arthropathies (
). In contrast, a separate study showed that the rs2910164 miR-146a allele was associated with increased psoriasis susceptibility in Han Chinese patients (
). 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 (
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 (
). Notably, the rs8259 BSG polymorphism was localized to the 3′ untranslated region miR-492-dependent binding site and completely abolished miR-492 binding (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
), 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 (
). 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 (
). 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 (
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 (
). 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 (
). 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 (
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 (
). 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 (
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.
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.
Laser capture microdissection followed by next-generation sequencing identifies disease-related microRNAs in psoriatic skin that reflect systemic microRNA changes in psoriasis.
Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock.
MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40.
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