Integrated Multi-Omics Profiling Reveals That Highly Pyroptotic MDMs Contribute to Psoriasis Progression Through CXCL16
<b>Background:</b> Psoriasis, an inflammatory skin disorder, involves pyroptosis—a pro-inflammatory cell death process. However, cell-specific pyroptosis dynamics and immune microenvironment interactions remain unclear. <b>Objective:</b> To investigate cell-type-specific pyro...
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2025-07-01
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| author | Liping Jin Xiaowen Xie Mi Zhang Wu Zhu Guanxiong Zhang Wangqing Chen |
| author_facet | Liping Jin Xiaowen Xie Mi Zhang Wu Zhu Guanxiong Zhang Wangqing Chen |
| author_sort | Liping Jin |
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| description | <b>Background:</b> Psoriasis, an inflammatory skin disorder, involves pyroptosis—a pro-inflammatory cell death process. However, cell-specific pyroptosis dynamics and immune microenvironment interactions remain unclear. <b>Objective:</b> To investigate cell-type-specific pyroptosis patterns in psoriasis and their immunoregulatory mechanisms. <b>Methods:</b> We integrated 21 transcriptomic datasets (from 2007 to 2020) obtained from the GEO database and two single-cell RNA sequencing datasets to quantify pyroptotic activity using Gene Set Variation Analysis and AUCell algorithms. Immune cell infiltration profiles were evaluated via CIBERSORT, while cell-cell communication networks were analyzed by CellChat. In vitro and in vivo experiments were performed to validate key findings. <b>Results:</b> Our analysis revealed that psoriasis patients exhibited significantly elevated levels of pyroptosis compared to healthy controls, with pyroptotic activity reflecting treatment responses. Notably, monocyte-derived macrophages (MDMs) in psoriatic lesions displayed markedly heightened pyroptotic activity. In vitro experiments confirmed that MDMs derived from psoriasis patients overexpressed pyroptosis-related molecules (Caspase 1 and Caspase 4) as well as pro-inflammatory cytokines (<i>TNFα</i>, <i>IL6</i>, <i>IL1β</i>) when compared to healthy controls. Furthermore, these cells showed increased expression of CXCL16, which might potentially activate Th17 cells through CXCR6 signaling, thereby driving skin inflammation. Inhibition of monocyte migration in an imiquimod-induced psoriasiform dermatitis model significantly alleviated skin inflammation and reduced the proportion of M1 macrophages and Th17 cells in lesional skin. <b>Conclusions:</b> This study revealed that MDMs in psoriatic lesions exhibited a hyperactive pyroptotic state, which contributed to disease progression through CXCL16-mediated remodeling of the immune microenvironment. These findings highlight pyroptosis as a potential therapeutic target for psoriasis. |
| format | Article |
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| spelling | doaj-art-07209f06363d49e382dc3a3ef5434ad52025-08-20T04:00:50ZengMDPI AGBiomedicines2227-90592025-07-01137176310.3390/biomedicines13071763Integrated Multi-Omics Profiling Reveals That Highly Pyroptotic MDMs Contribute to Psoriasis Progression Through CXCL16Liping Jin0Xiaowen Xie1Mi Zhang2Wu Zhu3Guanxiong Zhang4Wangqing Chen5Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China<b>Background:</b> Psoriasis, an inflammatory skin disorder, involves pyroptosis—a pro-inflammatory cell death process. However, cell-specific pyroptosis dynamics and immune microenvironment interactions remain unclear. <b>Objective:</b> To investigate cell-type-specific pyroptosis patterns in psoriasis and their immunoregulatory mechanisms. <b>Methods:</b> We integrated 21 transcriptomic datasets (from 2007 to 2020) obtained from the GEO database and two single-cell RNA sequencing datasets to quantify pyroptotic activity using Gene Set Variation Analysis and AUCell algorithms. Immune cell infiltration profiles were evaluated via CIBERSORT, while cell-cell communication networks were analyzed by CellChat. In vitro and in vivo experiments were performed to validate key findings. <b>Results:</b> Our analysis revealed that psoriasis patients exhibited significantly elevated levels of pyroptosis compared to healthy controls, with pyroptotic activity reflecting treatment responses. Notably, monocyte-derived macrophages (MDMs) in psoriatic lesions displayed markedly heightened pyroptotic activity. In vitro experiments confirmed that MDMs derived from psoriasis patients overexpressed pyroptosis-related molecules (Caspase 1 and Caspase 4) as well as pro-inflammatory cytokines (<i>TNFα</i>, <i>IL6</i>, <i>IL1β</i>) when compared to healthy controls. Furthermore, these cells showed increased expression of CXCL16, which might potentially activate Th17 cells through CXCR6 signaling, thereby driving skin inflammation. Inhibition of monocyte migration in an imiquimod-induced psoriasiform dermatitis model significantly alleviated skin inflammation and reduced the proportion of M1 macrophages and Th17 cells in lesional skin. <b>Conclusions:</b> This study revealed that MDMs in psoriatic lesions exhibited a hyperactive pyroptotic state, which contributed to disease progression through CXCL16-mediated remodeling of the immune microenvironment. These findings highlight pyroptosis as a potential therapeutic target for psoriasis.https://www.mdpi.com/2227-9059/13/7/1763pyroptosispsoriasisCXCL16monocyte-derived macrophagesmultiomics |
| spellingShingle | Liping Jin Xiaowen Xie Mi Zhang Wu Zhu Guanxiong Zhang Wangqing Chen Integrated Multi-Omics Profiling Reveals That Highly Pyroptotic MDMs Contribute to Psoriasis Progression Through CXCL16 Biomedicines pyroptosis psoriasis CXCL16 monocyte-derived macrophages multiomics |
| title | Integrated Multi-Omics Profiling Reveals That Highly Pyroptotic MDMs Contribute to Psoriasis Progression Through CXCL16 |
| title_full | Integrated Multi-Omics Profiling Reveals That Highly Pyroptotic MDMs Contribute to Psoriasis Progression Through CXCL16 |
| title_fullStr | Integrated Multi-Omics Profiling Reveals That Highly Pyroptotic MDMs Contribute to Psoriasis Progression Through CXCL16 |
| title_full_unstemmed | Integrated Multi-Omics Profiling Reveals That Highly Pyroptotic MDMs Contribute to Psoriasis Progression Through CXCL16 |
| title_short | Integrated Multi-Omics Profiling Reveals That Highly Pyroptotic MDMs Contribute to Psoriasis Progression Through CXCL16 |
| title_sort | integrated multi omics profiling reveals that highly pyroptotic mdms contribute to psoriasis progression through cxcl16 |
| topic | pyroptosis psoriasis CXCL16 monocyte-derived macrophages multiomics |
| url | https://www.mdpi.com/2227-9059/13/7/1763 |
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