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MAPK14 as a key gene for regulating inflammatory response and macrophage M1 polarization induced by ferroptotic keratinocyte in psoriasis

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Abstract

Psoriasis is a prevalent condition characterized by chronic inflammation, immune dysregulation, and genetic alterations, significantly impacting the well-being of affected individuals. Recently, a novel aspect of programmed cell death, ferroptosis, linked to iron metabolism, has come to light. This research endeavors to unveil novel diagnostic genes associated with ferroptosis in psoriasis, employing bioinformatic methods and experimental validation. Diverse analytical strategies, including "limma," Weighted Gene Co-expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine Recursive Feature Elimination (SVM-RFE), and Random Forest (RF), were employed to pinpoint pivotal ferroptosis-related diagnostic genes (FRDGs) in the training datasets GSE30999, testing dataset GSE41662 and GSE14905. The discriminative potential of FRDGs in distinguishing between normal and psoriatic patients was gauged using Receiver Operating Characteristic (ROC) curves, while the functional pathways of FRDGs were scrutinized through Gene Set Enrichment Analysis (GSEA). Spearman correlation and ssGSEA analysis were applied to explore correlations between FRDGs and immune cell infiltration or oxidative stress-related pathways. The study identified six robust FRDGs — PPARD, MAPK14, PARP9, POR, CDCA3, and PDK4 — which collectively formed a model boasting an exceptional AUC value of 0.994. GSEA analysis uncovered their active involvement in psoriasis-related pathways, and substantial correlations with immune cells and oxidative stress were noted. In vivo, experiments confirmed the consistency of the six FRDGs in the psoriasis model with microarray results. In vitro, genetic knockdown or inhibition of MAPK14 using SW203580 in keratinocytes attenuated ferroptosis and reduced the expression of inflammatory cytokines. Furthermore, the study revealed that intercellular communication between keratinocytes and macrophages was augmented by ferroptotic keratinocytes, increased M1 polarization, and recruitment of macrophage was regulated by MAPK14. In summary, our findings unveil novel ferroptosis-related targets and enhance the understanding of inflammatory responses in psoriasis. Targeting MAPK14 signaling in keratinocytes emerges as a promising therapeutic approach for managing psoriasis.

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Data availability statement

The series public data of GSE30999, GSE41662, and GSE162183 in the GEO database are available via the accession number. The corresponding authors can be contacted with questions about additional information in this study.

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Acknowledgements

Thanks a lot to the authors for their contribution to available gene expression profiles of microarrays and sc-RNA sequencing datasets in the GEO database.

Funding

The authors are grateful for the financial support received from The Science and Technology Project of Ganzhou (202101034530); The Foundation of Technology Innovation Team of First Affiliated Hospital of Gannan Medical University (2021CXTD-08); First Affiliated Hospital of Gannan Medical University, Doctor Start-up Fund (QD088).

Author information

Author notes

  1. Lin Zhou and Yingdong Zhong contributed equally to the paper, they were considered as the co-first authors.

Authors and Affiliations

  1. Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, Jiangxi, People’s Republic of China

    Lin Zhou, Lincai Li, Zhengwei Zou & Junsong Ye

  2. Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, Ganzhou, 341000, Jiangxi, People’s Republic of China

    Lin Zhou, Lincai Li, Zhengwei Zou & Junsong Ye

  3. Key Laboratory for Chemical Biology of Fujian Province, MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China

    Lin Zhou, Yu Zhou & Xi Liu

  4. Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, People’s Republic of China

    Lin Zhou, Lincai Li, Zhengwei Zou & Junsong Ye

  5. Key Laboratory of Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, 341000, Jiangxi, People’s Republic of China

    Lin Zhou, Lincai Li, Zhengwei Zou & Junsong Ye

  6. Department of Dermatology, Dongguan Liaobu Hospital, Dongguan, 523430, Guangdong, People’s Republic of China

    Yingdong Zhong

  7. Department of Dermatology, Gaozhou People’s Hospital, Gaozhou, 525200, Guangdong, People’s Republic of China

    Chaowei Li

  8. Center of Stem Cell and Regenerative Medicine, Gaozhou People’s Hospital, Gaozhou, Guangdong, 525200, China

    Zhihui Zhong

Authors
  1. Lin Zhou
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  2. Yingdong Zhong
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  3. Chaowei Li
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  4. Yu Zhou
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  5. Xi Liu
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  6. Lincai Li
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  7. Zhengwei Zou
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  8. Zhihui Zhong
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  9. Junsong Ye
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Contributions

Lin Zhou wrote the manuscript and Yingdong Zhong conducted bioinformatic analysis, they were considered as the co-first authors; Chaowei Li revised the manuscript; Yu Zhou and Xi Liu collected data from public databases and participated in building a psoriasis model; Lincai Li, and Zhengwei Zou cultured cell lines and carried out in vivo and vitro tests. Zhihui Zhong and Junsong Ye designed and organized the study. All authors contributed to the article and approved the final manuscript.

Corresponding authors

Correspondence to Zhihui Zhong or Junsong Ye.

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Conflict of interest

The authors all declare no potential conflicts of interest.

Ethics statement

The animal study was reviewed and approved by the Ethics Committee of First Affiliated Hospital of Gannan Medical University (No.LLSC-2023031501). The human data involved in this study was obtained from public datasets and did not involve the acquisition of tissue samples from humans, and the Ethics Committee of First Affiliated Hospital of Gannan Medical University agreed to waive human ethical approval.

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Zhou, L., Zhong, Y., Li, C. et al. MAPK14 as a key gene for regulating inflammatory response and macrophage M1 polarization induced by ferroptotic keratinocyte in psoriasis. Inflammation (2024). https://doi.org/10.1007/s10753-024-01994-8

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  • DOI: https://doi.org/10.1007/s10753-024-01994-8

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