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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageAmerican English
Article numbere15653
Pages (from-to)1-20
JournalEMBO Molecular Medicine
Volume14
Issue number8
DOIs
StatePublished - Aug 2022

Bibliographical note

Funding Information:
The authors are deeply grateful to Deborah Olam for excellent technical assistance, to Evelyne Zeira (z”l) who participated in initial aspects of this study, to SZ (Zami) Ben‐Sasson for providing IL‐1R mice, to Ron Apte (z”l) for IL‐17A mice, to Dr. Abed Nasereddin and Dr. Idit Shiff of the Genomic Applications Laboratory of The Core Research Facility, The Faculty of Medicine, The Hebrew University of Jerusalem, Israel, for 10× Genomics 3'‐scRNA‐seq library preparation and sequencing, to Yuhan Hao of the Satija lab for advice in using the Seurat software, to the amazing multi‐talented Alina Simerzin and Chofit Chai for artistic illustrations, to Nofar Rosenberg, Reba Condiotti, and Ittai Ben‐Porath for advice on p16INK4a immunostaining, and to Jacob (Kobi) Rachmilewitz and Avi‐Hai Hovav for helpful discussions on macrophages and dendritic cells. JHA is supported by grants from the Israel Ministry of Industry (Kamin 923/14) and the Israel Science Foundation (ISF 2201/20). EG is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) SFB841 project C3, the DKFZ‐MOST; the I‐CORE ISF center of excellence (41/11), and the ERC advance ‐ GA No. 786575. SRJ is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) SFB841 project C1; SFB877 project A1, and by the Cluster of Excellence “Precision Medicine in Chronic Inflammation”. Additional funding to EG was provided through the generosity of the Jay Ruskin Foundation, the Robert H. Benson Trust, and the Selma Kron Foundation for student fellowships. Mor Paldor was supported by a fellowship from the Naimi and Czarny families in memory of Nathan Naimi. knockout knockout

Funding Information:
The authors are deeply grateful to Deborah Olam for excellent technical assistance, to Evelyne Zeira (z”l) who participated in initial aspects of this study, to SZ (Zami) Ben-Sasson for providing IL-1R knockout mice, to Ron Apte (z”l) for IL-17A knockout mice, to Dr. Abed Nasereddin and Dr. Idit Shiff of the Genomic Applications Laboratory of The Core Research Facility, The Faculty of Medicine, The Hebrew University of Jerusalem, Israel, for 10× Genomics 3'-scRNA-seq library preparation and sequencing, to Yuhan Hao of the Satija lab for advice in using the Seurat software, to the amazing multi-talented Alina Simerzin and Chofit Chai for artistic illustrations, to Nofar Rosenberg, Reba Condiotti, and Ittai Ben-Porath for advice on p16INK4a immunostaining, and to Jacob (Kobi) Rachmilewitz and Avi-Hai Hovav for helpful discussions on macrophages and dendritic cells. JHA is supported by grants from the Israel Ministry of Industry (Kamin 923/14) and the Israel Science Foundation (ISF 2201/20). EG is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) SFB841 project C3, the DKFZ-MOST; the I-CORE ISF center of excellence (41/11), and the ERC advance - GA No. 786575. SRJ is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) SFB841 project C1; SFB877 project A1, and by the Cluster of Excellence “Precision Medicine in Chronic Inflammation”. Additional funding to EG was provided through the generosity of the Jay Ruskin Foundation, the Robert H. Benson Trust, and the Selma Kron Foundation for student fellowships. Mor Paldor was supported by a fellowship from the Naimi and Czarny families in memory of Nathan Naimi.

Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.

Keywords

  • CCR6
  • IL-6
  • alopecia
  • radiodermatitis
  • senescence

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