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LncRNA MIR4435-2HG promotes psoriatic inflammation via activation of PDGFRB-positive skin mesenchymal cells
doi: 10.1515/fzm-2026-0012
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Abstract:
Background Psoriasis is a chronic inflammatory skin disease influenced by genetic, immune, and environmental factors. Notably, its prevalence is significantly higher in colder regions, and cold climates are known to exacerbate disease symptoms. This study aimed to investigate the role of the long non-coding RNA MIR4435-2HG in regulating inflammation and cytokine production in psoriatic skin. Methods Single-cell RNA sequencing identified MIR4435-2HG expression in PDGFRB-positive mesenchymal cell subsets in psoriatic skin. Functional assays were performed to evaluate its effects on inflammatory cytokine expression in mesenchymal cells activated by TNF-α. An imiquimod-induced psoriasis mouse model was used to assess the effects of MIR4435-2HG knockdown in vivo. Results MIR4435-2HG was found to upregulate IL-6, CXCL8, and IL-17B expression in TNF-α-activated mesenchymal cells. Knockdown of MIR4435-2HG in the mouse model significantly reduced skin inflammation, epidermal hyperplasia, and psoriasis-associated cytokine expression. Conclusion MIR4435-2HG plays a critical role in regulating inflammation through mesenchymal cell activation, offering a potential therapeutic target for reducing psoriasis severity, especially in cold climates. -
Key words:
- psoriasis /
- mesenchymal cell /
- MIR4435-2HG
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Figure 1. Single-cell RNA sequencing data reveal specific expression of MIR4435-2HG in PDGFRB-positive mesenchymal cell clusters
(A) Schematic workflow illustrating the experimental design and analytical pipeline used in this study, designed by Figdraw2.0 (Home for Researchers, Hangzhou, China). (B) Box plot showing the relative expression of MIR4435-2HG across different skin cell clusters following updated classification. The x-axis represents cell cluster identities, and the y-axis indicates the relative expression level of MIR4435-2HG. Clusters selected for further investigation are highlighted in red. (C) Box plot comparing MIR4435-2HG expression between healthy and psoriatic mesenchymal cell clusters. (D) Box plot showing the relative expression of PDGFRB across different skin cell clusters. The x-axis represents cell cluster identities, and the y-axis indicates the relative expression level of PDGFRB. (E, F) UMAP plots illustrating the co-expression patterns of MIR4435-2HG and PDGFRB in skin cells. A substantial overlap in expression is observed within mesenchymal cell clusters. (G) Gene Ontology (GO) enrichment analysis of MIR4435-2HG-associated genes, highlighting their involvement in cellular responses to cytokine stimuli and cytokine signaling pathways.
Figure 2. Comparison of MIR4435-2HG expression in PDGFRB-positive mesenchymal cells between psoriatic and healthy skin
(A) Fluorescence in situ hybridization (FISH) analysis showing MIR4435-2HG expression (green) in human and mouse healthy and psoriatic skin. DAPI (blue) indicates nuclear staining. Yellow arrowheads indicate MIR4435-2HG-positive foci, and white dashed circles denote high-expression regions. Scale bar: 50 μm. N = 3 biological replicates. (B) Flow cytometry analysis of PDGFRB-positive mesenchymal cell proportions in skin tissues from patients with different psoriasis severities. Tyr751 represents PDGFRB-positive signals, FSC-A represents cell size, and the blue box indicates the proportion of PDGFRB-positive cells. N = 3 biological replicates. (C) Quantitative PCR (qPCR) analysis showing relative MIR4435-2HG mRNA expression in PDGFRB-positive cells isolated from healthy (CM/CH), mild psoriasis (mPM/mPH), and moderate-to-severe psoriasis (sPM/sPH) skin in both mice and humans. **P < 0.01; N = 9 biological replicates. CH, human healthy control; CM, mouse healthy control; PH, human psoriasis; PM, mouse psoriasis; mPH, mild psoriasis; sPH, moderate-to-severe psoriasis.
Figure 3. MIR4435-2HG regulates psoriasis-related cytokine expression in TNF-α-induced dermal mesenchymal cells
(A) Quantitative PCR (qPCR) analysis showing relative MIR4435-2HG mRNA expression in healthy dermal fibroblasts (HSF) and TNF-α-treated HSF cells (HSF-TNF). Data are presented as mean ± SEM. P < 0.01; N = 3 biological replicates. (B) qPCR validation of MIR4435-2HG knockdown in HSF cells using RNA interference (HSF-siRNA-TNF). The HSF-NC-TNF group served as a negative control. Data are presented as mean ± SEM. P < 0.01; N = 3 biological replicates. (C, D) qPCR and Western blot analyses showing the effects of MIR4435-2HG silencing on TNF-α-induced mRNA and protein expression of interleukin (IL)-6, IL-17B, and CXCL8 in HSF cells. Band intensities were normalized to β-actin. Molecular weight markers are indicated in kDa (kilodaltons). Data are presented as mean ± SEM. **P < 0.01; N = 3 biological replicates.
Figure 4. Suppressing MIR4435-2HG expression alleviates psoriasis severity in a murine model
(A, B) Representative images of dorsal skin and hematoxylin and eosin (H&E)-stained sections from healthy mice (CM), psoriasis model mice (PM), and siRNA-treated psoriasis mice (PM-siRNA). (C, D) Quantitative PCR (qPCR) and Western blot analyses showing the expression levels of interleukin (IL)-6, IL-17B, and CXCL8 in dermal cells isolated from dorsal skin across the three groups. Bar = 50 μm. Band intensities were normalized to β-actin. Molecular weight markers are indicated in kDa (kilodaltons). **P < 0.01; N = 3 biological replicates.
Figure 5. Mechanistic diagram illustrating the role of MIR4435-2HG in psoriasis pathogenesis
A schematic representation summarizing how MIR4435-2HG contributes to psoriasis pathogenesis through the activation of mesenchymal cells and the regulation of pro-inflammatory cytokine expression, including interleukin (IL)-6, IL-17B, and CXCL8. Designed by Figdraw2.0 (Home for Researchers, Hangzhou, China).
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