S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis
Abstract Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferation of keratinocytes and persistent inflammation. Although persistent activation of signal transducer and activator of transcription 3 (STAT3) is implicated in its pathogenesis, the mechanisms underlying the s...
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| Format: | Article |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07358-w |
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| author | Panpan Lian Li Li Renwei Lu Bin Zhang Junaid Wazir Chaode Gu Bojie Ma Wenyuan Pu Wangsen Cao Zhiqiang Huang Zhonglan Su Hongwei Wang |
| author_facet | Panpan Lian Li Li Renwei Lu Bin Zhang Junaid Wazir Chaode Gu Bojie Ma Wenyuan Pu Wangsen Cao Zhiqiang Huang Zhonglan Su Hongwei Wang |
| author_sort | Panpan Lian |
| collection | DOAJ |
| description | Abstract Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferation of keratinocytes and persistent inflammation. Although persistent activation of signal transducer and activator of transcription 3 (STAT3) is implicated in its pathogenesis, the mechanisms underlying the sustained STAT3 activation remain poorly understood. Here, we identify sphingosine-1-phosphate receptor 3 (S1PR3) as a critical regulator of STAT3 activation and psoriasis pathogenesis, orchestrating a self-amplifying circuit that sustains keratinocyte hyperproliferation and chronic inflammation. S1PR3 expression is markedly elevated in psoriatic lesions and correlates with disease severity. Using genetic and pharmacological approaches, we reveal a novel S1PR3–Src–STAT3 signaling axis that drives both early and prolonged STAT3 activation in keratinocytes. Mechanistically, S1PR3 operates through Gαi/PKA-mediated Src activation, enhancing STAT3 phosphorylation and subsequent transcriptional activity. Importantly, we reveal a previously unrecognized positive feedback loop wherein activated STAT3 directly upregulates S1PR3 expression, perpetuating inflammation and hyperproliferation. Genetic deletion of S1pr3 in mice or pharmacological inhibition of S1PR3 significantly attenuates psoriasis-like skin inflammation, decreasing epidermal hyperplasia, dermal angiogenesis, and inflammatory mediator production. These findings provide new insights into the molecular mechanisms underlying psoriasis and identify S1PR3 as a promising therapeutic target. Our study suggests that disrupting the S1PR3–STAT3 feedback loop may offer a novel strategy for treating psoriasis and potentially other chronic inflammatory diseases driven by persistent STAT3 activation. |
| format | Article |
| id | doaj-art-d3caade375034d27bddb19d97e607558 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-d3caade375034d27bddb19d97e6075582025-01-26T12:54:43ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111410.1038/s41419-025-07358-wS1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasisPanpan Lian0Li Li1Renwei Lu2Bin Zhang3Junaid Wazir4Chaode Gu5Bojie Ma6Wenyuan Pu7Wangsen Cao8Zhiqiang Huang9Zhonglan Su10Hongwei Wang11State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityState Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityState Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityCentral Laboratory, Nanjing Chest Hospital, Affiliated Nanjing Brain Hospital, Nanjing Medical UniversityState Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityState Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityState Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityState Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityState Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityState Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityDepartment of Dermatology, First Affiliated Hospital, Nanjing Medical UniversityState Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityAbstract Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferation of keratinocytes and persistent inflammation. Although persistent activation of signal transducer and activator of transcription 3 (STAT3) is implicated in its pathogenesis, the mechanisms underlying the sustained STAT3 activation remain poorly understood. Here, we identify sphingosine-1-phosphate receptor 3 (S1PR3) as a critical regulator of STAT3 activation and psoriasis pathogenesis, orchestrating a self-amplifying circuit that sustains keratinocyte hyperproliferation and chronic inflammation. S1PR3 expression is markedly elevated in psoriatic lesions and correlates with disease severity. Using genetic and pharmacological approaches, we reveal a novel S1PR3–Src–STAT3 signaling axis that drives both early and prolonged STAT3 activation in keratinocytes. Mechanistically, S1PR3 operates through Gαi/PKA-mediated Src activation, enhancing STAT3 phosphorylation and subsequent transcriptional activity. Importantly, we reveal a previously unrecognized positive feedback loop wherein activated STAT3 directly upregulates S1PR3 expression, perpetuating inflammation and hyperproliferation. Genetic deletion of S1pr3 in mice or pharmacological inhibition of S1PR3 significantly attenuates psoriasis-like skin inflammation, decreasing epidermal hyperplasia, dermal angiogenesis, and inflammatory mediator production. These findings provide new insights into the molecular mechanisms underlying psoriasis and identify S1PR3 as a promising therapeutic target. Our study suggests that disrupting the S1PR3–STAT3 feedback loop may offer a novel strategy for treating psoriasis and potentially other chronic inflammatory diseases driven by persistent STAT3 activation.https://doi.org/10.1038/s41419-025-07358-w |
| spellingShingle | Panpan Lian Li Li Renwei Lu Bin Zhang Junaid Wazir Chaode Gu Bojie Ma Wenyuan Pu Wangsen Cao Zhiqiang Huang Zhonglan Su Hongwei Wang S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis Cell Death and Disease |
| title | S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis |
| title_full | S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis |
| title_fullStr | S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis |
| title_full_unstemmed | S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis |
| title_short | S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis |
| title_sort | s1pr3 driven positive feedback loop sustains stat3 activation and keratinocyte hyperproliferation in psoriasis |
| url | https://doi.org/10.1038/s41419-025-07358-w |
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