Department of Dermatology, School of Medicine, Duke University, Durham, North Carolina, USA; Department of Molecular Genetics & Microbiology, School of Medicine, Duke University, Durham, North Carolina, USA.
Department of Dermatology, School of Medicine, Duke University, Durham, North Carolina, USA.
J Invest Dermatol. 2024 Dec;144(12):2742-2753. doi: 10.1016/j.jid.2024.04.017. Epub 2024 May 23.
UBE2N, a Lys63 ubiquitin-conjugating enzyme, plays critical roles in embryogenesis and immune system development and function. However, its roles in adult epithelial tissue homeostasis and pathogenesis are unclear. We generated conditional mouse models that deleted Ube2n in skin cells in a temporally and spatially controlled manner. We found that Ube2n knockout in the adult skin keratinocytes induced a range of inflammatory skin defects characteristic of psoriatic and actinic keratosis. These included inflammation, epidermal and dermal thickening, parakeratosis, and increased immune cell infiltration as well as signs of edema and blistering. Single-cell transcriptomic analyses and RT-qPCR showed that Ube2n-knockout keratinocytes expressed elevated myeloid cell chemoattractants such as Cxcl1 and Cxcl2 and decreased the homeostatic T lymphocyte chemoattractant Ccl27a. Consistently, the infiltrating immune cells were predominantly myeloid-derived cells, including neutrophils and M1-like macrophages, which expressed high levels of inflammatory cytokines such as Il1β and Il24. Pharmacological blockade of the IL-1 receptor associated kinases (IRAK1/4) alleviated inflammation, epidermal and dermal thickening, and immune infiltration of the Ube2n-mutant skin. Together, these findings highlight a key role of keratinocyte UBE2N in maintenance of epidermal homeostasis and skin immunity and identify IRAK1/4 as potential therapeutic target for inflammatory skin disorders.
UBE2N 是一种赖氨酸 63 泛素连接酶，在胚胎发生和免疫系统发育和功能中发挥着关键作用。然而，其在成年上皮组织稳态和发病机制中的作用尚不清楚。我们生成了条件性小鼠模型，可在时间和空间上控制地在皮肤细胞中敲除 Ube2n。我们发现，成年皮肤角质形成细胞中的 Ube2n 敲除会引起一系列具有银屑病和光化性角化病特征的炎症性皮肤缺陷。这些缺陷包括炎症、表皮和真皮增厚、角化不良以及免疫细胞浸润增加，还有水肿和水疱的迹象。单细胞转录组分析和 RT-qPCR 显示，Ube2n 敲除角质形成细胞表达高水平的髓样细胞趋化因子，如 Cxcl1 和 Cxcl2，同时降低了稳态 T 淋巴细胞趋化因子 Ccl27a。一致地，浸润的免疫细胞主要是髓样来源的细胞，包括中性粒细胞和 M1 样巨噬细胞，它们表达高水平的炎症细胞因子，如 Il1β 和 Il24。IL-1 受体相关激酶（IRAK1/4）的药理学阻断减轻了 Ube2n 突变皮肤的炎症、表皮和真皮增厚以及免疫浸润。总之，这些发现强调了角质形成细胞 UBE2N 在维持表皮稳态和皮肤免疫中的关键作用，并确定 IRAK1/4 是炎症性皮肤疾病的潜在治疗靶点。
