An Update on the Role of Long Non-Coding RNAs in Psoriasis

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An Update on the Role of Long Non-Coding RNAs in Psoriasis

Psoriasis is a chronic, immune-mediated inflammatory skin disorder characterized by epidermal hyperplasia, abnormal keratinocyte (KC) differentiation, and excessive angiogenesis. With a global prevalence ranging from 0.09% to 11.43%, psoriasis imposes significant economic burdens and comorbidities, including cardiovascular diseases, metabolic disorders, and autoimmune conditions. While the exact etiology remains elusive, dysregulation of immune responses involving dendritic cells (DCs), T cells, and KCs is central to its pathogenesis. Emerging evidence highlights long non-coding RNAs (lncRNAs) as critical regulators of gene expression at transcriptional, post-transcriptional, and translational levels. This review synthesizes recent findings on the roles of lncRNAs in psoriasis, focusing on their mechanisms in KCs, T cells, and DCs, and explores their potential as biomarkers and therapeutic targets.

LncRNAs in Keratinocyte Dysregulation

Keratinocytes are pivotal in maintaining epidermal homeostasis, but their hyperproliferation and impaired differentiation are hallmarks of psoriatic lesions. Aberrant expression of differentiation markers, such as reduced keratin K1/K10 and elevated K6/K16/K17, underscores KC dysfunction. LncRNAs modulate these processes through intricate molecular networks:

  1. LncRNA-MSX2P1:
    Upregulated in psoriatic lesions, MSX2P1 acts as a competing endogenous RNA (ceRNA) by sponging miR-6731-5p, thereby derepressing S100A7 (psoriasin). This promotes KC proliferation, inhibits apoptosis, and amplifies pro-inflammatory cytokines (IL-12b, IL-23, TNF-α) via NF-κB activation. IL-22 stimulation further elevates MSX2P1, linking it to psoriatic inflammation.

  2. MIR31HG:
    Overexpressed in psoriasis, MIR31HG drives KC proliferation by inducing G2/M phase arrest. Its expression is NF-κB-dependent, as cytokine stimulation (IL-17A, TNF-α) enhances its levels, while NF-κB inhibitors suppress it. This lncRNA represents a potential target for curbing hyperproliferation.

  3. LncRNA-H19:
    H19 promotes KC differentiation by sequestering miR-130b-3p, which otherwise suppresses desmoglein 1 (DSG1), a key protein for cell-cell adhesion. Calcium-induced differentiation upregulates H19, while miR-130b-3p inhibition restores DSG1 levels, highlighting H19’s role in maintaining epidermal integrity.

  4. RP6-65G23.1:
    This lncRNA is overexpressed in cytokine-stimulated KCs (IL-17A, TNF-α). Knockdown reduces proliferation, induces apoptosis, and arrests the cell cycle at G1/S by suppressing AKT and ERK1/2 signaling. Conversely, overexpression upregulates anti-apoptotic proteins Bcl-2 and Bcl-xL, exacerbating KC survival.

  5. MEG3:
    Downregulated in psoriasis, MEG3 inhibits KC proliferation by targeting miR-21, which normally represses caspase-8. MEG3 restoration increases caspase-8 and Bax (pro-apoptotic) while reducing Bcl-2, rebalancing apoptosis in psoriatic KCs.

  6. PRINS:
    Stress-inducible PRINS is elevated in non-lesional psoriatic epidermis, suggesting a susceptibility role. It regulates nucleophosmin (NPM) localization under UVB stress and modulates apoptosis via G1P3, an interferon-induced anti-apoptotic protein.

  7. HOTAIR and HULC:
    HOTAIR exacerbates UVB-induced KC apoptosis by upregulating PKR, activating pro-inflammatory cytokines (TNF-α, IL-6). HULC, via the JAK/STAT pathway, promotes BNIP3-mediated autophagy and apoptosis, aggravating UVB damage.

  8. PRANCR and LINC00941:
    PRANCR maintains KC proliferation by regulating the TP53-CDKN1A-DREAM-CHR pathway, while LINC00941 suppresses premature differentiation by inhibiting SPRR5, a positive regulator of epidermal differentiation.

LncRNAs in T Cell-Mediated Immunity

Psoriasis involves Th1/Th17 axis activation and Treg/Th17 imbalance. LncRNAs fine-tune T cell functions:

  1. FLICR:
    Expressed in regulatory T cells (Tregs), FLICR negatively regulates Foxp3, a master Treg transcription factor. FLICR deficiency stabilizes FoxP3 expression under low IL-2 conditions, enhancing Treg suppressive activity. This lncRNA thus modulates immune tolerance, with implications for autoimmune dysregulation in psoriasis.

  2. PRINS:
    Beyond KCs, PRINS is induced by T cell-derived cytokines (IFN-γ) in psoriatic epidermis, linking T cell activation to epidermal stress responses.

LncRNAs in Dendritic Cell Function

Dendritic cells bridge innate and adaptive immunity, driving psoriatic inflammation via T cell activation.

  1. MALAT1:
    Upregulated in LPS-stimulated DCs, MALAT1 promotes immune tolerance by enhancing DC-SIGN expression. It sponges miR-155, which represses PU.1, a DC-SIGN transcriptional activator. MALAT1-overexpressing DCs induce Treg differentiation and suppress effector T cells, suggesting a regulatory role in dampening inflammation.

LncRNAs as Potential Biomarkers

Genome-wide studies identify dysregulated lncRNAs in psoriatic tissues, offering diagnostic and prognostic potential:

  1. PSORS1C3:
    Located in the psoriasis susceptibility locus PSORS1, PSORS1C3 SNPs (e.g., rs15721489) correlate with disease risk, though linkage disequilibrium with HLA-Cw∗0602 complicates interpretation.

  2. ANRIL:
    SNPs (rs1333048, rs4977574, rs10757278) in this lncRNA, associated with immune diseases, show significant psoriasis risk. Haplotypes like C-A-G-A are protective, while C-A-G-G and T-C-G-G are risk-enhancing.

  3. CARD14 and Others:
    Overexpressed CARD14 lncRNA overlaps with CARD14, a NF-κB activator. SNPs (rs9902358) alter its secondary structure, potentially affecting function. Additional candidates like LINC00302 and LNC-AP000769.1-1:2 exhibit disease-specific expression patterns.

  4. Transcriptomic Signatures:
    RNA sequencing reveals 2,194 dysregulated lncRNAs in psoriatic lesions, including LNC-SLC6A14-1:1 (upregulated) and NONHSAT044111 (downregulated). Co-expression networks link lncRNAs to immune and differentiation pathways, with 40% of novel lncRNAs showing differential expression.

Therapeutic Implications and Challenges

LncRNAs offer novel therapeutic avenues but face hurdles:

  • Targeting Mechanisms: ceRNA networks (e.g., MSX2P1/miR-6731-5p/S100A7) and signaling pathways (NF-κB, AKT/ERK) provide intervention points.
  • Delivery Challenges: Nucleic acid-based therapies (antisense oligonucleotides, CRISPR) require efficient delivery systems to modulate lncRNAs in specific cell types.
  • Biomarker Development: Large-scale validation of lncRNA expression profiles and SNPs is needed for clinical translation.

Conclusion

LncRNAs are integral to psoriasis pathogenesis, regulating KC proliferation, immune cell activation, and inflammatory cascades. Their roles as ceRNAs, epigenetic modifiers, and signaling modulators underscore their therapeutic potential. Future research must clarify causal relationships, optimize delivery mechanisms, and validate biomarkers across diverse populations. Integrating lncRNA biology into psoriasis management could revolutionize treatment strategies, addressing unmet needs in this complex disease.

doi.org/10.1097/CM9.0000000000001243

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