Single cell analysis reveals a complex cellular and molecular crosstalk involving a crucial IL-6/CCR6 axis in irradiation-induced alopecia and dermatitis

Background: Hair loss (Alopecia) and dermatitis are two of the most common outwardly recognizable and debilitating complications of radiotherapy. In mice, similar to human patients, irradiation exposure induces widespread dermatitis beginning at about 10-14 days, which is characterized by neutrophil infiltration, distinct infiltration of CD3⁺ T cells into the hair follicles and ultimately by widespread, albeit temporary, alopecia.

Methods: Here we applied 10x Genomics based single cell RNAseq analysis to characterize the cellular and molecular interactions underlying the development of irradiation-induced alopecia and dermatitis (IRIAD) in female C57BL/6 mice irradiated with 15 Gy to the head and neck in a single-fraction dose.

Results: We demonstrate that IRIAD is highly dependent upon an apparent cellular and molecular cross-talk involving IL-6 originating from fibroblasts, keratinocytes and basal cells, IL-1β expressed by monocytes and macrophages, type 17 mediated cytokines (IL-17, IL-22) from T cells and chemokines (CCR6) expressed by T cells and CCL20 originating from keratinocytes and basal cells. IL-6 deficiency or blockade prevented IL-17, IL-22, CCL20 and CCR6 upregulation, and ablation of CCR6 abolished both IL-6 and MHC class I upregulation together with infiltration of CD3⁺ T cells into the hair follicle; while disruption of either IL-6 or CCR6 dramatically prevented IRIAD. Therapeutically, IRIAD was effectively prevented by cyclosporine and partially by topical application of pharmacological inhibitors of Janus kinases.

Conclusion: These findings point to the complexity of the inflammatory response underlying IRIAD and the clinical potential of IL-6/CCR6 targeted therapeutics for its prevention.