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Dermal adipogenesis protects against neutrophilic skin inflammation during psoriasis pathogenesis

Cellular & Molecular Immunology (2025)Cite this article

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Abstract

The immune response of the skin to danger signals involves rapid recruitment of neutrophils, but their excessive accumulation leads to inflammatory skin diseases, such as psoriasis; however, the mechanisms governing their initiation and resolution are poorly understood. Here, we revealed a dynamic immunoregulatory role of dermal white adipose tissue (dWAT) in the progression and resolution of neutrophilic skin inflammation in an imiquimod-induced psoriasis mouse model. During inflammation onset, dWAT repopulates PDGFRA+ preadipocytes (pAds), which secrete CXCL1 and SAA3, attracting and activating CXCR2+ neutrophils. These neutrophils further activate pAds through the IL-1R-NFκB-C/EBPδ pathway, establishing a self-sustaining inflammatory loop. Paradoxically, prolonged IL-1β signaling triggers PPARγ-dependent adipogenesis, transitioning pAds into anti-inflammatory early adipocytes that resolve neutrophilic inflammation via lipid mediators. Inhibition of adipogenesis, via pharmacological or genetic inhibition of PPARγ, disrupts the formation of early adipocytes, prevents neutrophil regression, and exacerbates inflammation. Analysis of human psoriatic cells revealed a C/EBPδ+ dermal fibroblast (dFB) subpopulation enriched with preadipocytes, the IL-1 pathway, and inflammatory gene signatures. Furthermore, transcriptomic analyses revealed a negative correlation between the neutrophil-related inflammatory response and the dermal lipogenesis response in generalized pustular psoriasis. Together, our findings reveal the dual role of dWAT: PDGFRA+ pAds initiate inflammation via CXCL1/IL-1β crosstalk with neutrophils, whereas PPARγ-driven adipogenesis resolves this process through lipid mediators. This work establishes dWAT as a critical immunomodulatory hub and proposes adipogenic reprogramming of proinflammatory fibroblasts or topical delivery of early adipocyte lipids as innovative therapies for neutrophil-driven skin diseases, such as psoriasis and ulcers.

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Acknowledgements

L-JZ is supported by the National Key R&D Program of China (2023YFC2508102), the National Natural Science Foundation of China (82373879), the Fujian Provincial Natural Science Foundation of China (2024J011009), and the Xiamen University Double First Class Construction Project (Biology) (DFC2024004). R. W. is supported by the Yunnan University Medical Research Foundation (YDYXJJ2024-0022) and Yunnan Provincial Department of Education Scientific Research Fund Project (2025J0020). We thank Dr. Jiahuai Han from Xiamen University for providing the IL1r1-/- mice and Dr. Yuling Shi from Fudan University for providing the Pparg-floxed mice. We thank the flow cytometry and confocal microscopic core facility at Xiamen University for flow cytometry, sorting and imaging studies.

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Author notes

  1. These authors contributed equally: Tian Xia, Wenlu Zhang, Rundong Wu.

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China

    Tian Xia, Wenlu Zhang, Rundong Wu, Xiaowei Zhang, Rongshuang Xia, Xiao Hu, Yanhang Liao, Jiacheng Li, Youxi Liu, Wenjie Liu & Ling-juan Zhang

  2. Department of Clinical Pharmacy, The Affiliated Hospital of Yunnan University, Kunming, China

    Rundong Wu

  3. State Key Laboratory of Cellular Stress Biology, School of Biological Sciences, Xiamen University, Xiamen, 361102, China

    Shuai Wu & Yiman Liu

  4. Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China

    Zhuolin Guo, Jiajing Lu & Yuling Shi

  5. State-Province Joint Engineering Laboratory of Marine Bioproducts and Technology, Department of Marine Biological Science & Technology, College of Ocean & Earth Sciences, Xiamen University, Xiamen, 361102, China

    Chi Zhang & Ming Chen

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  1. Tian Xia
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  2. Wenlu Zhang
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Contributions

Conceptualization, TX, WZ, RW, MC, and LZ; methodology, TX, WZ, RW, XZ, RX, CZ, WL, and LZ; investigation, TX, WZ, RW, XhangZ, RX, XH, SW, YanhangL, JL, YouxiL, YimanL, ZG, and WL; resources, MC, JL, and YS; data curation, TX, WZ, RW, and LZ; writing-original draft, TX, WZ, RW, and LZ; writing-review and editing, MC, JL, YS, and LZ; supervision, LZ.

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Correspondence to Ling-juan Zhang.

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Xia, T., Zhang, W., Wu, R. et al. Dermal adipogenesis protects against neutrophilic skin inflammation during psoriasis pathogenesis. Cell Mol Immunol (2025). https://doi.org/10.1038/s41423-025-01296-5

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