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Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C–C Motif Chemokine Ligand 20
Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity response to skin contact allergens in which keratinocytes are critical in the initiation of early responses. Keratin 17 (K17) is a cytoskeletal protein inducible under stressful conditions and regulates multiple cellular processes,...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8845002/ https://www.ncbi.nlm.nih.gov/pubmed/35178048 http://dx.doi.org/10.3389/fimmu.2022.764793 |
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author | Luo, Yixin Zhu, Zhenlai Li, Bing Bai, Xiaocui Fang, Hui Qiao, Pei Chen, Jiaoling Zhang, Chen Zhi, Dalong Dang, Erle Wang, Gang |
author_facet | Luo, Yixin Zhu, Zhenlai Li, Bing Bai, Xiaocui Fang, Hui Qiao, Pei Chen, Jiaoling Zhang, Chen Zhi, Dalong Dang, Erle Wang, Gang |
author_sort | Luo, Yixin |
collection | PubMed |
description | Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity response to skin contact allergens in which keratinocytes are critical in the initiation of early responses. Keratin 17 (K17) is a cytoskeletal protein inducible under stressful conditions and regulates multiple cellular processes, especially in skin inflammatory diseases; however, knowledge regarding its contribution to ACD pathogenesis remains ill defined. In the present study, we clarified the proinflammatory role of K17 in an oxazolone (OXA)-induced contact hypersensitivity (CHS) murine model and identified the underlying molecular mechanisms. Our results showed that K17 was highly expressed in the lesional skin of ACD patients and OXA-induced CHS mice. Mice lacking K17 exhibited alleviated OXA-induced skin inflammation, including milder ear swelling, a reduced frequency of T cell infiltration, and decreased inflammatory cytokine levels. In vitro, K17 stimulated and activated human keratinocytes to produce plenty of proinflammatory mediators, especially the chemokine CCL20, and promoted keratinocyte-mediated T cell trafficking. The neutralization of CCL20 with a CCL20-neutralizing monoclonal antibody significantly alleviated OXA-induced skin inflammation in vivo. Moreover, K17 could translocate into the nucleus of activated keratinocytes through a process dependent on the nuclear-localization signal (NLS) and nuclear-export signal (NES) sequences, thus facilitating the activation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3), further promoting the production of CCL20 and T cell trafficking to the lesional skin. Taken together, these results highlight the novel roles of K17 in driving allergen-induced skin inflammation and suggest targeting K17 as a potential strategy for ACD. |
format | Online Article Text |
id | pubmed-8845002 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-88450022022-02-16 Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C–C Motif Chemokine Ligand 20 Luo, Yixin Zhu, Zhenlai Li, Bing Bai, Xiaocui Fang, Hui Qiao, Pei Chen, Jiaoling Zhang, Chen Zhi, Dalong Dang, Erle Wang, Gang Front Immunol Immunology Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity response to skin contact allergens in which keratinocytes are critical in the initiation of early responses. Keratin 17 (K17) is a cytoskeletal protein inducible under stressful conditions and regulates multiple cellular processes, especially in skin inflammatory diseases; however, knowledge regarding its contribution to ACD pathogenesis remains ill defined. In the present study, we clarified the proinflammatory role of K17 in an oxazolone (OXA)-induced contact hypersensitivity (CHS) murine model and identified the underlying molecular mechanisms. Our results showed that K17 was highly expressed in the lesional skin of ACD patients and OXA-induced CHS mice. Mice lacking K17 exhibited alleviated OXA-induced skin inflammation, including milder ear swelling, a reduced frequency of T cell infiltration, and decreased inflammatory cytokine levels. In vitro, K17 stimulated and activated human keratinocytes to produce plenty of proinflammatory mediators, especially the chemokine CCL20, and promoted keratinocyte-mediated T cell trafficking. The neutralization of CCL20 with a CCL20-neutralizing monoclonal antibody significantly alleviated OXA-induced skin inflammation in vivo. Moreover, K17 could translocate into the nucleus of activated keratinocytes through a process dependent on the nuclear-localization signal (NLS) and nuclear-export signal (NES) sequences, thus facilitating the activation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3), further promoting the production of CCL20 and T cell trafficking to the lesional skin. Taken together, these results highlight the novel roles of K17 in driving allergen-induced skin inflammation and suggest targeting K17 as a potential strategy for ACD. Frontiers Media S.A. 2022-02-01 /pmc/articles/PMC8845002/ /pubmed/35178048 http://dx.doi.org/10.3389/fimmu.2022.764793 Text en Copyright © 2022 Luo, Zhu, Li, Bai, Fang, Qiao, Chen, Zhang, Zhi, Dang and Wang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Luo, Yixin Zhu, Zhenlai Li, Bing Bai, Xiaocui Fang, Hui Qiao, Pei Chen, Jiaoling Zhang, Chen Zhi, Dalong Dang, Erle Wang, Gang Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C–C Motif Chemokine Ligand 20 |
title | Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C–C Motif Chemokine Ligand 20 |
title_full | Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C–C Motif Chemokine Ligand 20 |
title_fullStr | Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C–C Motif Chemokine Ligand 20 |
title_full_unstemmed | Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C–C Motif Chemokine Ligand 20 |
title_short | Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C–C Motif Chemokine Ligand 20 |
title_sort | keratin 17 promotes t cell response in allergic contact dermatitis by upregulating c–c motif chemokine ligand 20 |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8845002/ https://www.ncbi.nlm.nih.gov/pubmed/35178048 http://dx.doi.org/10.3389/fimmu.2022.764793 |
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