Radiation Exposure Perturbs IL-17RA-Mediated Immunity Leading to Changes in Neutrophil Responses That Increase Susceptibility to Oropharyngeal Candidiasis

Abstract

Fungal infections caused by Candida albicans are a serious problem for immunocompromised individuals, including those undergoing radiotherapy for head and neck cancers. Targeted irradiation causes inflammatory dysregulation and damage to the oral mucosa that can be exacerbated by candidiasis. Post-irradiation the cytokine interleukin-17 (IL-17) protects the oral mucosae by promoting oral epithelial regeneration and balancing the oral immune cell populations, which leads to the eventual healing of the tissue. IL-17 signaling is also critical for the antifungal response during oropharyngeal candidiasis (OPC). Yet, the benefit of IL-17 during other forms of candidiasis, such as vulvovaginal candidiasis, is not straightforward. Therefore, it was important to determine the role of IL-17 during OPC associated with radiation-induced inflammatory damage. To answer this question, we exposed Il17ra−/− and wild-type mice to head-neck irradiation (HNI) and OPC to determine if the IL-17 signaling pathway was still protective against C. albicans. HNI increased susceptibility to OPC, and in Il17ra−/− mice, the mucosal damage and fungal burden were elevated compared to control mice. Intriguingly, neutrophil influx was increased in Il17ra−/− mice, yet these cells had reduced capacity to phagocytose C. albicans and failed to clear OPC compared to immunocompetent mice. These findings suggest that radiotherapy not only causes physical damage to the oral cavity but also skews immune mediators, leading to increased susceptibility to oropharyngeal candidiasis.