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

Area of Science:

• Immunology
• Oncology
• Oral Medicine

Background:

• Oral mucositis (OM) is a severe side effect of cancer treatments like radiation and chemotherapy.
• It affects up to 80% of head and neck cancer patients, with limited understanding of its healing mechanisms.
• Current knowledge of OM immunopathogenesis is insufficient for developing effective treatments.

Purpose of the Study:

• To investigate the role of Interleukin-17 (IL-17) in the immunopathogenesis and healing of oral mucositis (OM).
• To establish a clinically relevant murine model for studying OM mechanisms and therapeutic development.
• To elucidate the specific pathways involved in IL-17-mediated protection against OM.

Main Methods:

• Utilized a murine model mimicking human oral mucositis induced by head and neck irradiation (HNI).
• Performed RNA sequencing (RNAseq) on oral tissues to analyze gene expression changes.
• Compared OM severity and healing in wild-type mice versus those lacking the IL-17 receptor (IL-17RA).
• Investigated neutrophil recruitment and activation pathways, including IL-1R signaling.

Main Results:

• Head and neck irradiation (HNI) increased IL-17 expression in the oral mucosa.
• Mice lacking IL-17RA showed significantly more severe OM with impaired mucosal restoration.
• Absence of IL-17RA led to excessive, IL-1R-driven neutrophil recruitment and immunopathology.
• IL-17RA deficiency reduced healing-associated factors like matrix metalloproteinases (MMP3, MMP10) and IL-24.
• Blocking IL-1R and depleting neutrophils reduced OM severity in IL-17RA deficient mice.

Conclusions:

• IL-17 plays a protective role in oral mucositis (OM) by promoting epithelial healing and regulating neutrophil responses.
• The study identified a novel mechanism where IL-17 controls detrimental neutrophil activity in OM.
• The developed murine model offers a valuable platform for understanding OM and testing new therapies.