The Role of Interleukin-17 in Tissue Protection during Radiation-Induced Oral Mucositis

Abstract

<h3>Purpose/Objective(s)</h3> Oral mucositis (OM) is a common non-hematological side effect of radiotherapy and chemotherapy for head and neck cancers. Tissue injury associated with OM is painful, and can be difficult to treat. While the clinical progression of OM is understood, the signaling networks involved in the progression and resolution of damage have not been fully elucidated. Interleukin-17 (IL-17) is a proinflammatory cytokine produced by ‘type-17' lymphocytes, including T-helper 17 (Th17) cells. IL-17 is important in host protection against microbes, but it also can be pathogenic in autoimmune conditions. The role of IL-17 in other inflammatory disorders is not straightforward either. Due to the proliferative and inflammatory properties of IL-17 it is implicated in several malignancies, including esophageal cancer and tongue squamous cell carcinoma. Yet, in the distal gastrointestinal tract, IL-17 can be protective in tissue repair and maintenance. We set out to determine the role of IL-17 during severe ulceration of the oral mucosa associated with head and neck irradiation. We hypothesized that IL-17 is beneficial in repair of the oral mucosa after radiation exposure. <h3>Materials/Methods</h3> We approached this question by exposing wild-type (WT) mice and mice deficient in the receptor for IL-17, IL-17RA (<i>Il17ra</i>^−/−), to head and neck irradiation (HNI)-induced OM. Mice received a single dose of 22.5Gy of targeted irradiation using 6 MeV electrons from a linear accelerator. Tongue tissue was excised and processed for RNA-Seq analysis. The tissue was assessed macroscopically and histologically for damage, and the immune cells present in the oral tissue after HNI were determined by flow cytometry. <h3>Results</h3> RNA-Seq of oral tissue showed elevated expression of IL-17 and related immune pathways in response to HNI. Mice lacking IL-17RA exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in the <i>Il17ra</i>^−/- mice and components associated with healing were diminished. The absence of IL-17RA also resulted in excess neutrophils and immunopathology compared to WT mice. <h3>Conclusion</h3> IL-17RA is required to prevent severe mucosal damage, and optimize healing after ionizing radiation. IL-17RA contributes to the proliferative capacity of the oral epithelia and maintains immune cell balance in the oral mucosa creating an environment conducive to restoration of the damaged tissue. This important contribution of IL-17 post-irradiation has implications for other cancer therapies related to the Th17 pathway.