Juan Manuel Leyva-Castillo, Mrinmoy Das, Maria Strakosha, Alex McGurk, Emilie Artru, Christy Kam, Mohammed Alasharee, Duane R Wesemann, Michio Tomura, Hajime Karasuyama, Frank Brombacher, Raif S Geha
{"title":"IL-4 作用于皮肤衍生的树突状细胞，促进 Th2 对皮肤过敏的反应，并引发过敏性皮肤炎症。","authors":"Juan Manuel Leyva-Castillo, Mrinmoy Das, Maria Strakosha, Alex McGurk, Emilie Artru, Christy Kam, Mohammed Alasharee, Duane R Wesemann, Michio Tomura, Hajime Karasuyama, Frank Brombacher, Raif S Geha","doi":"10.1016/j.jaci.2024.06.021","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Atopic dermatitis is characterized by scratching and a T<sub>H</sub>2-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.</p><p><strong>Objective: </strong>We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the T<sub>H</sub>2 response to cutaneously encountered antigen and allergic skin inflammation.</p><p><strong>Methods: </strong>DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4<sup>+</sup> 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.</p><p><strong>Results: </strong>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 T<sub>H</sub>2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4<sup>-/-</sup> mice and CD11c-CreIl4r<sup>flox/-</sup> mice, which lack IL-4Rα expression in DCs (DC<sup>Δ/Δll4ra</sup> mice), were impaired in their capacity to drive T<sub>H</sub>2 polarization compared with DCs from controls. Importantly, OVA-sensitized DC<sup>Δ/Δll4ra</sup> mice demonstrated impaired allergic skin inflammation and OVA-specific systemic T<sub>H</sub>2 response evidenced by reduced T<sub>H</sub>2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls.</p><p><strong>Conclusions: </strong>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 T<sub>H</sub>2 polarization and drive allergic skin inflammation.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":"1462-1471.e3"},"PeriodicalIF":11.4000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625010/pdf/","citationCount":"0","resultStr":"{\"title\":\"IL-4 acts on skin-derived dendritic cells to promote the T<sub>H</sub>2 response to cutaneous sensitization and the development of allergic skin inflammation.\",\"authors\":\"Juan Manuel Leyva-Castillo, Mrinmoy Das, Maria Strakosha, Alex McGurk, Emilie Artru, Christy Kam, Mohammed Alasharee, Duane R Wesemann, Michio Tomura, Hajime Karasuyama, Frank Brombacher, Raif S Geha\",\"doi\":\"10.1016/j.jaci.2024.06.021\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Atopic dermatitis is characterized by scratching and a T<sub>H</sub>2-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.</p><p><strong>Objective: </strong>We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the T<sub>H</sub>2 response to cutaneously encountered antigen and allergic skin inflammation.</p><p><strong>Methods: </strong>DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4<sup>+</sup> 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.</p><p><strong>Results: </strong>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 T<sub>H</sub>2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4<sup>-/-</sup> mice and CD11c-CreIl4r<sup>flox/-</sup> mice, which lack IL-4Rα expression in DCs (DC<sup>Δ/Δll4ra</sup> mice), were impaired in their capacity to drive T<sub>H</sub>2 polarization compared with DCs from controls. Importantly, OVA-sensitized DC<sup>Δ/Δll4ra</sup> mice demonstrated impaired allergic skin inflammation and OVA-specific systemic T<sub>H</sub>2 response evidenced by reduced T<sub>H</sub>2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls.</p><p><strong>Conclusions: </strong>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 T<sub>H</sub>2 polarization and drive allergic skin inflammation.</p>\",\"PeriodicalId\":14936,\"journal\":{\"name\":\"Journal of Allergy and Clinical Immunology\",\"volume\":\" \",\"pages\":\"1462-1471.e3\"},\"PeriodicalIF\":11.4000,\"publicationDate\":\"2024-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625010/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Allergy and Clinical Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jaci.2024.06.021\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/10 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ALLERGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jaci.2024.06.021","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/10 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
IL-4 acts on skin-derived dendritic cells to promote the TH2 response to cutaneous sensitization and the development of allergic skin inflammation.
Background: Atopic dermatitis is characterized by scratching and a TH2-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.
Objective: We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the TH2 response to cutaneously encountered antigen and allergic skin inflammation.
Methods: 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.
Results: 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 TH2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4-/- mice and CD11c-CreIl4rflox/- mice, which lack IL-4Rα expression in DCs (DCΔ/Δll4ra mice), were impaired in their capacity to drive TH2 polarization compared with DCs from controls. Importantly, OVA-sensitized DCΔ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic TH2 response evidenced by reduced TH2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls.
Conclusions: 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 TH2 polarization and drive allergic skin inflammation.
期刊介绍：
The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.
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