| Autor: |
Winge, Mårten C. G., Nasrallah, Mazen, Jackrazi, Leandra V., Guo, Konnie Q., Fuhriman, Jessica M., Szafran, Rebecca, Ramanathan, Muthukumar, Gurevich, Irina, Nguyen, Ngon T., Siprashvili, Zurab, Inayathullah, Mohammed, Rajadas, Jayakumar, Porter, Douglas F., Khavari, Paul A., Butte, Atul J., Marinkovich, M. Peter |
| Zdroj: |
Science Translational Medicine; 12/11/2024, Vol. 16 Issue 777, p1-16, 16p |
| Abstrakt: |
Inflammatory skin disease is characterized by a pathologic interplay between skin cells and immunocytes and can result in disfiguring cutaneous lesions and systemic inflammation. Immunosuppression is commonly used to target the inflammatory component; however, these drugs are often expensive and associated with side effects. To identify previously unidentified targets, we carried out a nonbiased informatics screen to identify drug compounds with an inverse transcriptional signature to keratinocyte inflammatory signals. Using psoriasis, a prototypic inflammatory skin disease, as a model, we used pharmacologic, transcriptomic, and proteomic characterization to find that benzamil, the benzyl derivative of the US Food and Drug Administration–approved diuretic amiloride, effectively reversed keratinocyte-driven inflammatory signaling. Through three independent mouse models of skin inflammation (Rac1G12V transgenic mice, topical imiquimod, and human skin xenografts from patients with psoriasis), we found that benzamil disrupted pathogenic interactions between the small GTPase Rac1 and its adaptor NCK1. This reduced STAT3 and NF-κB signaling and downstream cytokine production in keratinocytes. Genetic knockdown of sodium channels or pharmacological inhibition by benzamil prevented excess Rac1-NCK1 binding and limited proinflammatory signaling pathway activation in patient-derived keratinocytes without systemic immunosuppression. Both systemic and topical applications of benzamil were efficacious, suggesting that it may be a potential therapeutic avenue for treating skin inflammation. Editor's summary: Inflammatory skin diseases such as psoriasis are typically treated with immunosuppressants, but side effects and cost limit their use. Here, Winge et al. computationally screened a library of existing drugs to identify compounds that could limit inflammatory gene expression in keratinocytes. They found that benzamil, a precursor of the sodium channel blocker amiloride, reduced skin inflammation by reducing intracellular pH to disrupt Rac1 signaling and its interaction with NCK1. The authors confirmed its efficacy in two mouse models of psoriasiform inflammation and human skin xenograft models. These results suggest that benzamil may be a potential treatment for patients with psoriasis to limit inflammation without immune suppression. —Allison Williams [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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