期刊
EMBO MOLECULAR MEDICINE
卷 14, 期 8, 页码 -出版社
WILEY
DOI: 10.15252/emmm.202115653
关键词
radiodermatitis; alopecia; senescence; IL-6; CCR6
资金
- Israel Ministry of Industry [923/14]
- Israel Science Foundation [ISF 2201/20]
- Deutsche Forschungsgemeinschaft (DFG) [SFB841, SFB877]
- I-CORE ISF center of excellence [41/11]
- ERC [786575]
- Cluster of Excellence Precision Medicine in Chronic Inflammation
- Jay Ruskin Foundation
- Robert H. Benson Trust
- Selma Kron Foundation
- Naimi family
- DKFZ-MOST
- Czarny family
- European Research Council (ERC) [786575] Funding Source: European Research Council (ERC)
This study reveals the molecular and cellular basis of irradiation-induced alopecia and dermatitis (IRIAD). Senescence-associated IL-6 and IL-1 signaling, IL-17 upregulation, and CCR6(+)-mediated immune cell migration are the key drivers of IRIAD. Genetic ablation and molecular inhibition of these pathways alleviate IRIAD symptoms.
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.
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