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Background <p>Risankizumab was an approved novel drug by Japan for psoriasis, we aimed to explore its underlying therapeutic mechanism through the single-cell RNA&#xa0;sequencing (scRNA-seq) technology.</p> Methods <p>ScRNA-seq data (GSE228421) were obtained from the Gene Expression Omnibus (GEO) database. Quality control, normalization, clustering, and cell-type annotation were performed using the R packages Seurat and harmony, together with the CellMarker2.0 database. Differentially expressed genes (DEGs) were identified using the FindMarkers function, and functional enrichment analysis of DEGs was conducted with the ClusterProfiler R package. Cell differentiation trajectories were inferred by pseudo-time analysis using the Monocle2 package. In addition, THP-1 monocytes were differentiated into macrophages and treated with different concentrations of risankizumab. Cell viability was assessed by CCK-8 assay, while cytokine production (TNF-α, IL-1β, IL-6, IL-4, IL-10, and IL-13) was measured using ELISA to evaluate the effects of risankizumab on inflammatory responses and macrophage polarization.</p> Results <p>A total of 97,434 cells were analyzed and divided into eight major clusters. Among them, myeloid cells showed the most significant reduction following risankizumab treatment, suggesting that they may be the primary target of the therapy in psoriasis. Functional enrichment analysis revealed that antibacterial humoral response, antimicrobial humoral response, and keratinization activities in myeloid cells were markedly inhibited. Further analysis identified three macrophage subtypes, and risankizumab treatment was found to promote differentiation of anti-inflammatory IL10⁺ M2 macrophages while reducing IL6⁺ M1 macrophages, thereby contributing to the control of psoriasis. Consistently, in-vitro experiments demonstrated that risankizumab suppressed the production of pro-inflammatory cytokines and enhanced M2 macrophage polarization, confirming its immunomodulatory role.</p> Conclusions <p>This study reveals that risankizumab exerts its anti-inflammatory effects by inhibiting M1-type and promoting M2-type macrophage polarization, thereby elucidating its key mechanism for treating psoriasis and providing theoretical support for novel immunotherapy targets.</p>

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Single-cell RNA sequencing and in vitro validation reveal risankizumab induces anti-inflammatory macrophage polarization in psoriasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月12日

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  • Yuan Yuan,
  • Linzi Li,
  • Lihong Yang,
  • Jiyuan Zheng,
  • Guang Gao,
  • Ting Tan,
  • Jing Liu,
  • Wen Sun

摘要

Background

Risankizumab was an approved novel drug by Japan for psoriasis, we aimed to explore its underlying therapeutic mechanism through the single-cell RNA sequencing (scRNA-seq) technology.

Methods

ScRNA-seq data (GSE228421) were obtained from the Gene Expression Omnibus (GEO) database. Quality control, normalization, clustering, and cell-type annotation were performed using the R packages Seurat and harmony, together with the CellMarker2.0 database. Differentially expressed genes (DEGs) were identified using the FindMarkers function, and functional enrichment analysis of DEGs was conducted with the ClusterProfiler R package. Cell differentiation trajectories were inferred by pseudo-time analysis using the Monocle2 package. In addition, THP-1 monocytes were differentiated into macrophages and treated with different concentrations of risankizumab. Cell viability was assessed by CCK-8 assay, while cytokine production (TNF-α, IL-1β, IL-6, IL-4, IL-10, and IL-13) was measured using ELISA to evaluate the effects of risankizumab on inflammatory responses and macrophage polarization.

Results

A total of 97,434 cells were analyzed and divided into eight major clusters. Among them, myeloid cells showed the most significant reduction following risankizumab treatment, suggesting that they may be the primary target of the therapy in psoriasis. Functional enrichment analysis revealed that antibacterial humoral response, antimicrobial humoral response, and keratinization activities in myeloid cells were markedly inhibited. Further analysis identified three macrophage subtypes, and risankizumab treatment was found to promote differentiation of anti-inflammatory IL10⁺ M2 macrophages while reducing IL6⁺ M1 macrophages, thereby contributing to the control of psoriasis. Consistently, in-vitro experiments demonstrated that risankizumab suppressed the production of pro-inflammatory cytokines and enhanced M2 macrophage polarization, confirming its immunomodulatory role.

Conclusions

This study reveals that risankizumab exerts its anti-inflammatory effects by inhibiting M1-type and promoting M2-type macrophage polarization, thereby elucidating its key mechanism for treating psoriasis and providing theoretical support for novel immunotherapy targets.