Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling.

Jessica Saul-Mcbeth,Heather R Conti,Priosmita Biswas,Allen G Schroering,Dylan Launder,Vincent M Bruno,E Ishmael Parsai,Grace Michalski,Samuel R Conti,Amol C Shetty,Alexandria A Williamson,Carrie Mccracken,Aaron Lee,John Dillon,Jacqueline M Kratch,Eanas Abutaha

doi:10.3389/fimmu.2021.687627

Jessica Saul-Mcbeth, Heather R Conti + Show 14 more

Open Access

https://doi.org/10.3389/fimmu.2021.687627

Copy DOI

Abstract

Oral mucositis (OM) is a treatment-limiting adverse side effect of radiation and chemotherapy. Approximately 80% of patients undergoing radiotherapy (RT) for head and neck cancers (HNC) develop OM, representing a major unmet medical condition. Our understanding of the immunopathogenesis of OM is limited, due in part to the surprising paucity of information regarding healing mechanisms in the oral mucosa. RNAseq of oral tissue in a murine model that closely mimics human OM, showed elevated expression of IL-17 and related immune pathways in response to head and neck irradiation (HNI). Strikingly, mice lacking the IL-17 receptor (IL-17RA) exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in Il17ra−/− mice and components associated with healing, including matrix metalloproteinase 3, 10 and IL-24 were diminished. IL-17 is typically associated with recruitment of neutrophils to mucosal sites following oral infections. Unexpectedly, in OM the absence of IL-17RA resulted in excessive neutrophil recruitment and immunopathology. Instead, neutrophil activation was IL-1R-driven in Il17ra−/− mice. Blockade of IL-1R and depletion of neutrophils lessened the severity of damage in these mice. Overall, we show IL-17 is protective in OM through multiple mechanisms including restoration of the damaged epithelia and control of the neutrophil response. We also present a clinically relevant murine model of human OM to improve mechanistic understanding and develop rational translational therapeutics.

Highlights

Oral mucositis (OM) is one of the most common non-hematological side effects of radiotherapy (RT) and/or chemotherapy for head and neck cancers (HNC), characterized by tissue injury of the oral mucosae [1]
Most patients with HNC are treated with external beam radiotherapy using a relatively newer modality known as Intensity Modulation Radiotherapy (IMRT)
These treatment planning systems contain optimization routines for inverse planning to achieve optimal dose to the target volume while sparing normal tissue. All of these newer features have been instrumental in reducing the severity of OM in recent years, but we still consider this as a major side effect of radiation for HNC patients that needs to be dealt with [35]

Summary

Introduction

Oral mucositis (OM) is one of the most common non-hematological side effects of radiotherapy (RT) and/or chemotherapy for head and neck cancers (HNC), characterized by tissue injury of the oral mucosae [1]. OM is painful and associated with nutritional deficiency, resulting in a large economic burden due to costs and clinical risks associated with pain management and liquid diet supplementation [2]. IL-17RA Is Tissue-Protective in Oral Mucositis increases 3.9-fold [3]. The current therapeutic options for OM are largely ineffective and management relies on lessening symptoms, not prevention [6,7,8,9]. Severe OM can lead to increased hospitalizations and the use of feeding tubes, which may interrupt or alter cancer therapy leading to worse tumor outcomes [2, 6, 10,11,12]

Methods

Results

Conclusion