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

Area of Science:

• Oncology
• Dermatology
• Immunology

Background:

• Irradiation-induced alopecia and dermatitis (IRIAD) are common radiotherapy side effects.
• The underlying molecular mechanisms of IRIAD are not well understood.

Purpose of the Study:

• To elucidate the molecular and cellular basis of irradiation-induced alopecia and dermatitis (IRIAD).
• To identify potential therapeutic targets for managing radiotherapy-induced skin damage.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of irradiated skin cells.
• Genetic ablation studies in IL-6 knockout (IL-6-/-) and IL-1 receptor knockout (IL-1R-/-) mice.
• Molecular inhibition studies and CCR6 knockout (CCR6-/-) mouse models.
• Bioinformatics analysis to identify signaling pathways and cell types involved.

Main Results:

• Senescence-associated IL-6 and IL-1 signaling, along with IL-17 upregulation and CCR6+ immune cell migration, were identified as key drivers of IRIAD.
• IL-6 signaling was localized to hair follicles, basal keratinocytes, and dermal fibroblasts.
• Genetic or molecular blockade of IL-6, IL-1, or CCR6 pathways significantly ameliorated IRIAD.
• IL-6 deficiency reduced IL-17, IL-22, CCL20, and CCR6; CCR6 deficiency reduced IL-6, IL-17, CCL3, and MHC, indicating cellular cross-talk.

Conclusions:

• Targeting IL-6, IL-1, and CCR6-mediated pathways can mitigate IRIAD.
• Topical Janus kinase inhibitors and cyclosporine show therapeutic potential for radiotherapy-induced skin side effects.