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

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 À/À or IL-1R À/À mice, or by molecular blockade, strongly ameliorated IRIAD, as did deficiency of CCL20/CCR6mediated immune cell migration in CCR6 À/À 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.

Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD

“…The absence of a significant response in tissues such as the lung and colon suggest the possibility that these organs did not have a substantial pool of senescent cells following total body irradiation and allogeneic transplantation, as observed with the non-significant change in IL-6 mRNA in the colon and IL-6 and IL-8 mRNAs in the lung tissue (Figure 5A,B). While the source of the senescent pool is still being investigated, based on a recent report [41] and data presented in this work, it is plausible that DQ mitigates the effect of irradiation followed by allogeneic transplantation on the senescent cell pool and SASP-like factors that promote aberrant immune activation in the host tissues/organs. This would limit subsequent organ damage and other systemic effects associated with cGVHD.…”

“…Interestingly, alopecia and other changes in the skin are classical hallmarks of radiationinduced DNA damage that triggers inflammation as well as promotes the acquisition of senescence and SASP [41]. Together, inflammatory mediators (IL-17 and CCL20) and SASP factors such as IL-1 and IL-6 function in a self-amplifying loop to induce alopecia and dermatitis in irradiated animals [41]. Interestingly, senescence and SASP induction have been closely associated with the pathogenesis of cGVHD [7,42].…”

Nomogram based on circulating lymphocyte subsets for predicting radiation pneumonia in esophageal squamous cell carcinoma

“…It is widely accepted that radiotherapy could induce a marked immune response and the release of proinflammatory cytokines by immune cells ( 29 – 31 ). Actually, RP is a kind of immune-mediated hypersensitive pneumonia ( 32 ).…”

An evaluation of statistical differential analysis methods in single-cell RNA-seq data

“…Single-cell RNA sequencing becomes increasingly popular in biological and biomedical research to examine gene regulatory relationships, identify cell populations and senescent cells in the aging process, and gene expression differences associated with different treatments or diseases ( [1,2]). Different from bulk RNA sequencing experiments, single-cell RNA sequencing experiments isolate and sequence individual cells extracted from normal tissues or tissues with diseases ( [3][4][5][6][7]).…”