Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; Institute for Immunology and Infectious Diseases, Yonsei University College of Medicine, Seoul, Korea.
J Dermatol Sci. 2024 Jul;115(1):2-12. doi: 10.1016/j.jdermsci.2024.05.002. Epub 2024 May 9.
Atopic dermatitis (AD), a chronic inflammatory skin disease with T cell activation as a key feature, in which Th2 cell-mediated responses play a pivotal role. Regulatory T cells (Treg) are central immune cells that restrict autoimmunity and inflammation in the body. Patients with immune dysregulation, polyendocrinopathy, or enteropathy X-linked syndrome, an immune disease characterized by a deficiency in Treg, develop skin inflammation and allergic disorders, indicating that Treg play a crucial role in the development of allergic skin inflammation.
we investigated the underlying mechanisms by which Treg control cutaneous allergic inflammation.
An allergic skin inflammation mouse model was constructed using MC903, and Treg-depleted mouse model was constructed using diphtheria toxin. Neutralization of IFN-γ was constructed using anti-mouse-IFN-γ mouse antibody. Neutrophil infiltration was analyzed by flow cytometry and immunohistochemistry. Neutrophil extracellular traps (NETs), a process called NETosis, were detected using immunofluorescence. In vitro neutrophil stimulation and immunocytochemistry was conducted to demonstrate the effect of IFN-γ on NETosis.
The depletion of Foxp3 Treg led to significantly exacerbated AD-like skin inflammation, including increased recruitment of neutrophils and expression of Th1 cytokine IFN-γ. Neutrophil infiltrating in skin of Treg-depleted mice released more NETs than wild type. Neutralization of IFN-γ abolished neutrophil infiltration and NETosis in Treg-depleted mice. Neutrophils stimulated with IFN-γ were more prone to release NETs in vitro. Finally, Foxp3 Treg control cutaneous allergic inflammation by regulating IFN-γ-driven neutrophilic infiltration and NETosis.
Our results highlight the previously underestimated Treg-IFN-γ-neutrophil inflammatory axis.
特应性皮炎（AD）是一种慢性炎症性皮肤病，其特征是 T 细胞激活，其中 Th2 细胞介导的反应起着关键作用。调节性 T 细胞（Treg）是限制体内自身免疫和炎症的核心免疫细胞。患有免疫失调、多发性内分泌腺病或肠病 X 连锁综合征（一种以 Treg 缺乏为特征的免疫性疾病）的患者会出现皮肤炎症和过敏疾病，这表明 Treg 在过敏性皮肤炎症的发展中起着至关重要的作用。
我们研究了 Treg 控制皮肤过敏炎症的潜在机制。
使用 MC903 构建过敏性皮肤炎症小鼠模型，使用白喉毒素构建 Treg 耗竭小鼠模型。使用抗小鼠 IFN-γ 单克隆抗体中和 IFN-γ。通过流式细胞术和免疫组织化学分析中性粒细胞浸润。通过免疫荧光检测中性粒细胞胞外陷阱（NETs），即 NETosis 过程。进行体外中性粒细胞刺激和免疫细胞化学，以证明 IFN-γ 对 NETosis 的影响。
Foxp3 Treg 的耗竭导致类似于 AD 的皮肤炎症明显加重，包括中性粒细胞募集增加和 Th1 细胞因子 IFN-γ 的表达增加。Treg 耗竭小鼠皮肤中浸润的中性粒细胞释放的 NETs 多于野生型。中和 IFN-γ 可消除 Treg 耗竭小鼠中的中性粒细胞浸润和 NETosis。体外用 IFN-γ 刺激的中性粒细胞更倾向于释放 NETs。最后，Foxp3 Treg 通过调节 IFN-γ 驱动的中性粒细胞浸润和 NETosis来控制皮肤过敏炎症。
我们的结果强调了以前被低估的 Treg-IFN-γ-中性粒细胞炎症轴。
