| Autor: |
Kang I, Ko, Jean J, Merlet, Brett P, DerGarabedian, Huang, Zhen, Yoko, Suzuki-Horiuchi, Matthew L, Hedberg, Eileen, Hu, Anh T, Nguyen, Stephen, Prouty, Faizan, Alawi, Matthew C, Walsh, Yongwon, Choi, Sarah E, Millar, Ashley, Cliff, Jonathon, Romero, Michael R, Garvin, John T, Seykora, Daniel, Jacobson, Dana T, Graves |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Sci Transl Med |
| ISSN: |
1946-6242 |
| Popis: |
Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Upregulation of the Nuclear factor-kappa B pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single cell RNA sequencing data via iterative Random Forest Leave One Out Prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique Prx1(+) fibroblast subpopulation. Disruption of Ikkb-NF-kB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C Motif Chemokine Ligand 11 (CCL11, or eotaxin-1) characterized by eosinophil infiltration and a subsequent Th2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined validated human AD skin samples and found that human AD fibroblasts also over-expressed CCL11 and that perturbation of Ikkb-NFkB in primary human dermal fibroblasts upregulates CCL11. We also demonstrated that monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and Th2 inflammation in a mouse model. Taken together, the murine model and human AD specimens point to dysregulated Prx1(+) fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest targeting CCL11 as a way to treat AD-like skin lesions. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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