Diminished γδ T Cells during Murine Allergic Skin Inflammation Is Mediated by IL-4 Signaling in Keratinocytes.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Wenwu Zhang, Abigail Pajulas, Michelle Niese, Hongming Zhou, Jennifer Zhao, Nahid Akhtar, Matthew J Turner, Mark H Kaplan
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Abstract

Atopic dermatitis results in diminished barrier function and altered production of antimicrobial peptides. Dendritic epidermal T cells (DETCs) play an important role in the wound repair and inflammation process. Our previous work identified an IL-4-dependent loss of DETCs in Stat6VT mice and in the MC903-induced skin inflammation mouse model. However, the mechanisms through which IL-4 mediates the loss of DETCs are unclear. In this study, we show that IL-4Rα germline knockout mice (Il4ra-/-) have increased DETCs, faster wound healing, and increased epidermal differentiation complex gene and fibronectin expression. The absence of IL-4Rα minimized the MC903-induced loss of DETCs, and reciprocal bone marrow chimera experiments in Il4ra-/- and wild-type mice demonstrated structural nonhematopoietic IL-4-responsive cell-mediated DETC homeostasis. Skin keratinocyte-derived IL-15 decreased dramatically in the MC903 model, while injection of IL-15 rescued DETC loss by promoting DETC proliferation and limiting apoptosis. Conditional deletion of IL-4Rα from keratinocytes using Il4rafl/fl K14-Cre mice showed an increase of DETCs, increased IL-15 production, and diminished skin inflammation following wounding. These results suggest that IL-4-dependent effects on DETCs in allergic skin inflammation are mediated by the IL-4Rα receptor of keratinocytes.

小鼠过敏性皮肤炎症期间γδ T 细胞的减少是由角质形成细胞中的 IL-4 信号介导的
特应性皮炎会导致屏障功能减弱和抗菌肽的产生发生改变。树突状表皮 T 细胞(DETCs)在伤口修复和炎症过程中发挥着重要作用。我们之前的研究发现,在 Stat6VT 小鼠和 MC903 诱导的皮肤炎症小鼠模型中,DETCs 的损失依赖于 IL-4。然而,IL-4介导DETCs损失的机制尚不清楚。在本研究中,我们发现 IL-4Rα 基因敲除小鼠(Il4ra-/-)的 DETCs 增加,伤口愈合更快,表皮分化复合物基因和纤维连接蛋白表达增加。Il4ra-/-和野生型小鼠的骨髓嵌合实验表明,非造血IL-4反应细胞介导的DETC平衡结构。在 MC903 模型中,皮肤角质细胞衍生的 IL-15 显著减少,而注射 IL-15 则可通过促进 DETC 增殖和限制细胞凋亡来挽救 DETC 的丧失。利用Il4rafl/fl K14-Cre小鼠从角质形成细胞中条件性缺失IL-4Rα,结果显示DETC增加、IL-15产生增加,并减轻了伤口后的皮肤炎症。这些结果表明,在过敏性皮肤炎症中,IL-4对DETCs的依赖性作用是由角质形成细胞的IL-4Rα受体介导的。
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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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