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

7 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
JournalEMBO Molecular Medicine
Volume14
Issue number8
DOIs
StatePublished - 8 Aug 2022

Bibliographical note

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

Keywords

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

Fingerprint

Dive into the research topics of 'Single-cell transcriptomics reveals a senescence-associated IL-6/CCR6 axis driving radiodermatitis'. Together they form a unique fingerprint.

Cite this