Crisaborole efficacy in murine models of skin inflammation and Staphylococcus aureus infection.
Crisaborole efficacy in murine models of skin inflammation and Staphylococcus aureus infection.
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Crisaborole 在皮肤炎症和金黄色葡萄球菌感染的小鼠模型中的功效。
DOI：
10.1111/exd.14722
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发表时间：
2023
影响因子：
3.6
通讯作者：
Archer,NathanK
中科院分区：
文献类型：
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作者：
Youn,Christine;Dikeman,DustinA;Chang,Evelyn;Liu,Haiyun;Nolan,SabrinaJ;Alphonse,MartinP;Joyce,DanielP;Liu,Qi;Meixiong,James;Dong,Xinzhong;Miller,LloydS;Archer,NathanK
磷酸二酯酶4(PDE4)在角质形成细胞和免疫细胞中高表达，并在激活后促进促炎反应。PDE4的活性被归因于各种炎症条件，导致了PDE4抑制剂作为宿主导向疗法在人类中的开发和批准。例如，外用PDE4抑制剂Crisborole已被批准用于治疗轻至中度特应性皮炎，并已显示出对牛皮癣患者的疗效。然而，Crisborole在调节炎症性皮肤病和感染的免疫发病机制中的作用并不完全清楚。因此，我们评估了Crisborole在多种小鼠模型中的作用，包括牛皮癣样皮炎、伴有和不伴有微丝蛋白突变的AD样皮炎，以及金黄色葡萄球菌感染。我们发现，在牛皮癣样皮炎期间，Crisborole会抑制髓系细胞，并使皮肤发痒。此外，在细丝蛋白缺乏的情况下，Crisborole在减少皮肤炎症方面是有效的。重要的是，Crisborole降低了S。阿尔茨海默病样皮肤炎症期间金黄色皮肤的定植。然而，Crisborole对S的治疗效果不佳。金黄色皮肤感染，甚至作为抗生素的辅助治疗。综上所述，我们发现Crisborole在银屑病样皮炎期间减少了瘙痒，并减少了S。金黄色皮肤在类AD皮肤炎症中的定植，这是Crisborole抑制炎症性皮肤病小鼠模型的免疫病理机制的额外机制。有必要进行进一步的检查，以将这些临床前发现转化为人类疾病。
Phosphodiesterase 4 (PDE4) is highly expressed in keratinocytes and immune cells and promotes pro‐inflammatory responses upon activation. The activity of PDE4 has been attributed to various inflammatory conditions, leading to the development and approval of PDE4 inhibitors as host‐directed therapeutics in humans. For example, the topical PDE4 inhibitor, crisaborole, is approved for the treatment of mild‐to‐moderate atopic dermatitis and has shown efficacy in patients with psoriasis. However, the role of crisaborole in regulating the immunopathogenesis of inflammatory skin diseases and infection is not entirely known. Therefore, we evaluated the effects of crisaborole in multiple mouse models, including psoriasis‐like dermatitis, AD‐like skin inflammation with and without filaggrin mutations, andStaphylococcus aureusskin infection. We discovered that crisaborole dampens myeloid cells and itch in the skin during psoriasis‐like dermatitis. Furthermore, crisaborole was effective in reducing skin inflammation in the context of filaggrin deficiency. Importantly, crisaborole reducedS. aureusskin colonization during AD‐like skin inflammation. However, crisaborole was not efficacious in treatingS. aureusskin infections, even as adjunctive therapy to antibiotics. Taken together, we found that crisaborole reduced itch during psoriasis‐like dermatitis and decreasedS. aureusskin colonization upon AD‐like skin inflammation, which act as additional mechanisms by which crisaborole dampens the immunopathogenesis in mouse models of inflammatory skin diseases. Further examination is warranted to translate these preclinical findings to human disease.