Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis
Abstract Irradiation‐induced alopecia and dermatitis (IRIAD) are two of the most visually recognized complications of radiotherapy, of which the molecular and cellular basis remains largely unclear. By combining scRNA‐seq analysis of whole skin‐derived irradiated cells with genetic ablation and mole...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-08-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202115653 |
| _version_ | 1797280715576967168 |
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| author | Mor Paldor Orr Levkovitch‐Siany Dana Eidelshtein Revital Adar Claes D Enk Yitzhak Marmary Sharona Elgavish Yuval Nevo Hadar Benyamini Inbar Plaschkes Shiri Klein Alex Mali Stefan Rose‐John Amnon Peled Eithan Galun Jonathan H Axelrod |
| author_facet | Mor Paldor Orr Levkovitch‐Siany Dana Eidelshtein Revital Adar Claes D Enk Yitzhak Marmary Sharona Elgavish Yuval Nevo Hadar Benyamini Inbar Plaschkes Shiri Klein Alex Mali Stefan Rose‐John Amnon Peled Eithan Galun Jonathan H Axelrod |
| author_sort | Mor Paldor |
| collection | DOAJ |
| description | Abstract Irradiation‐induced alopecia and dermatitis (IRIAD) are two of the most visually recognized complications of radiotherapy, of which the molecular and cellular basis remains largely unclear. By combining scRNA‐seq analysis of whole skin‐derived irradiated cells with genetic ablation and molecular inhibition studies, we show that senescence‐associated IL‐6 and IL‐1 signaling, together with IL‐17 upregulation and CCR6+‐mediated immune cell migration, are crucial drivers of IRIAD. Bioinformatics analysis colocalized irradiation‐induced IL‐6 signaling with senescence pathway upregulation largely within epidermal hair follicles, basal keratinocytes, and dermal fibroblasts. Loss of cytokine signaling by genetic ablation in IL‐6−/− or IL‐1R−/− mice, or by molecular blockade, strongly ameliorated IRIAD, as did deficiency of CCL20/CCR6‐mediated immune cell migration in CCR6−/− mice. Moreover, IL‐6 deficiency strongly reduced IL‐17, IL‐22, CCL20, and CCR6 upregulation, whereas CCR6 deficiency reciprocally diminished IL‐6, IL‐17, CCL3, and MHC upregulation, suggesting that proximity‐dependent cellular cross talk promotes IRIAD. Therapeutically, topical application of Janus kinase blockers or inhibition of T‐cell activation by cyclosporine effectively reduced IRIAD, suggesting the potential of targeted approaches for the treatment of dermal side effects in radiotherapy patients. |
| first_indexed | 2024-03-07T16:45:03Z |
| format | Article |
| id | doaj.art-5a050c8736134d50b74c2fbb8dbbdcf4 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:45:03Z |
| publishDate | 2022-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-5a050c8736134d50b74c2fbb8dbbdcf42024-03-03T06:38:06ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-08-01148n/an/a10.15252/emmm.202115653Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitisMor Paldor0Orr Levkovitch‐Siany1Dana Eidelshtein2Revital Adar3Claes D Enk4Yitzhak Marmary5Sharona Elgavish6Yuval Nevo7Hadar Benyamini8Inbar Plaschkes9Shiri Klein10Alex Mali11Stefan Rose‐John12Amnon Peled13Eithan Galun14Jonathan H Axelrod15The Goldyne‐Savad Institute of Gene Therapy Hadassah Hebrew University Hospital Jerusalem IsraelThe Goldyne‐Savad Institute of Gene Therapy Hadassah Hebrew University Hospital Jerusalem IsraelThe Goldyne‐Savad Institute of Gene Therapy Hadassah Hebrew University Hospital Jerusalem IsraelThe Goldyne‐Savad Institute of Gene Therapy Hadassah Hebrew University Hospital Jerusalem IsraelDepartment of Dermatology Hadassah Hebrew University Hospital Jerusalem IsraelThe Goldyne‐Savad Institute of Gene Therapy Hadassah Hebrew University Hospital Jerusalem IsraelInfo‐CORE, Bioinformatics Unit of the I‐CORE Hebrew University of Jerusalem Jerusalem IsraelInfo‐CORE, Bioinformatics Unit of the I‐CORE Hebrew University of Jerusalem Jerusalem IsraelInfo‐CORE, Bioinformatics Unit of the I‐CORE Hebrew University of Jerusalem Jerusalem IsraelInfo‐CORE, Bioinformatics Unit of the I‐CORE Hebrew University of Jerusalem Jerusalem IsraelThe Goldyne‐Savad Institute of Gene Therapy Hadassah Hebrew University Hospital Jerusalem IsraelDepartment of Pathology Hadassah Hebrew University Hospital Jerusalem IsraelInstitut für Biochemie Christian‐Albrechts‐Universität zu Kiel Kiel GermanyThe Goldyne‐Savad Institute of Gene Therapy Hadassah Hebrew University Hospital Jerusalem IsraelThe Goldyne‐Savad Institute of Gene Therapy Hadassah Hebrew University Hospital Jerusalem IsraelThe Goldyne‐Savad Institute of Gene Therapy Hadassah Hebrew University Hospital Jerusalem IsraelAbstract Irradiation‐induced alopecia and dermatitis (IRIAD) are two of the most visually recognized complications of radiotherapy, of which the molecular and cellular basis remains largely unclear. By combining scRNA‐seq analysis of whole skin‐derived irradiated cells with genetic ablation and molecular inhibition studies, we show that senescence‐associated IL‐6 and IL‐1 signaling, together with IL‐17 upregulation and CCR6+‐mediated immune cell migration, are crucial drivers of IRIAD. Bioinformatics analysis colocalized irradiation‐induced IL‐6 signaling with senescence pathway upregulation largely within epidermal hair follicles, basal keratinocytes, and dermal fibroblasts. Loss of cytokine signaling by genetic ablation in IL‐6−/− or IL‐1R−/− mice, or by molecular blockade, strongly ameliorated IRIAD, as did deficiency of CCL20/CCR6‐mediated immune cell migration in CCR6−/− mice. Moreover, IL‐6 deficiency strongly reduced IL‐17, IL‐22, CCL20, and CCR6 upregulation, whereas CCR6 deficiency reciprocally diminished IL‐6, IL‐17, CCL3, and MHC upregulation, suggesting that proximity‐dependent cellular cross talk promotes IRIAD. Therapeutically, topical application of Janus kinase blockers or inhibition of T‐cell activation by cyclosporine effectively reduced IRIAD, suggesting the potential of targeted approaches for the treatment of dermal side effects in radiotherapy patients.https://doi.org/10.15252/emmm.202115653radiodermatitisalopeciasenescenceIL‐6CCR6 |
| spellingShingle | Mor Paldor Orr Levkovitch‐Siany Dana Eidelshtein Revital Adar Claes D Enk Yitzhak Marmary Sharona Elgavish Yuval Nevo Hadar Benyamini Inbar Plaschkes Shiri Klein Alex Mali Stefan Rose‐John Amnon Peled Eithan Galun Jonathan H Axelrod Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis EMBO Molecular Medicine radiodermatitis alopecia senescence IL‐6 CCR6 |
| title | Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis |
| title_full | Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis |
| title_fullStr | Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis |
| title_full_unstemmed | Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis |
| title_short | Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis |
| title_sort | single cell transcriptomics reveals a senescence associated il 6 ccr6 axis driving radiodermatitis |
| topic | radiodermatitis alopecia senescence IL‐6 CCR6 |
| url | https://doi.org/10.15252/emmm.202115653 |
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