Leyva-Castillo Juan Manuel, Das Mrinmoy, Strakosha Maria, McGurk Alex, Artru Emilie, Kam Christy, Alasharee Mohammed, Wesemann Duane R, Tomura Michio, Karasuyama Hajime, Brombacher Frank, Geha Raif S
Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Mass.
Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Boston, Mass.
J Allergy Clin Immunol. 2024 Dec;154(6):1462-1471.e3. doi: 10.1016/j.jaci.2024.06.021. Epub 2024 Jul 10.
Atopic dermatitis is characterized by scratching and a T2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells.
We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the T2 response to cutaneously encountered antigen and allergic skin inflammation.
DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4 T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA.
Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. In vitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive T2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4 mice and CD11c-CreIl4r mice, which lack IL-4Rα expression in DCs (DC mice), were impaired in their capacity to drive T2 polarization compared with DCs from controls. Importantly, OVA-sensitized DC mice demonstrated impaired allergic skin inflammation and OVA-specific systemic T2 response evidenced by reduced T2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls.
Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for T2 polarization and drive allergic skin inflammation.
特应性皮炎的特征是搔抓以及对经皮肤接触的抗原产生以T2为主的局部和全身反应。树突状细胞（DCs）在皮肤中捕获抗原，并迅速迁移至引流淋巴结（dLNs），在那里它们驱动抗原特异性初始T细胞的分化。
我们试图确定非T细胞来源的白细胞介素-4（IL-4）是否作用于皮肤来源的DCs，以促进对经皮肤接触抗原的T2反应和过敏性皮肤炎症。
通过流式细胞术分析来自暴露于卵清蛋白（OVA）皮肤的dLNs中的DCs，并检测其使OVA特异性初始CD4 T细胞极化的能力。通过皮肤细胞的流式细胞术和细胞因子的实时定量聚合酶链反应评估胶带剥离皮肤经皮致敏后的皮肤炎症。通过酶联免疫吸附测定（ELISA）评估细胞因子分泌和抗体水平。
搔抓上调了人皮肤中IL4的表达。同样，胶带剥离导致小鼠皮肤中依赖嗜碱性粒细胞的皮肤Il4表达迅速上调。用IL-4体外处理来自皮肤dLNs的DCs可促进其驱动T2分化的能力。与对照组的DCs相比，来自Il4小鼠和CD11c-CreIl4r小鼠（DC小鼠，其DCs中缺乏IL-4Rα表达）的OVA致敏皮肤dLNs中的DCs驱动T2极化的能力受损。重要的是，与对照组相比，OVA致敏的DC小鼠表现出过敏性皮肤炎症受损以及OVA特异性全身T响应受损，这表现为OVA刺激的脾细胞分泌的T2细胞因子减少以及OVA特异性IgE和IgG1抗体水平降低。
机械性皮肤损伤导致依赖嗜碱性粒细胞的皮肤IL-4上调。IL-4作用于捕获抗原并迁移至dLNs的皮肤DCs，以促进其T2极化能力并驱动过敏性皮肤炎症。
