Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis

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...

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Main Authors: 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
Format: Article
Language:English
Published: Springer Nature 2022-07-01
Series:EMBO Molecular Medicine
Subjects:
radiodermatitis
alopecia
senescence
IL‐6
CCR6
Online Access:https://doi.org/10.15252/emmm.202115653
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Summary: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.
ISSN:1757-4676
1757-4684

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