The Role of the Innate Immune Response in Oral Mucositis Pathogenesis

Abstract

Oral mucositis (OM) is a significant complication of cancer therapy with limited management strategies. Whilst inflammation is a central feature of destructive and ultimately ulcerative pathology, to date, attempts to mitigate damage via this mechanism have proven limited. A relatively underexamined aspect of OM development is the contribution of elements of the innate immune system. In particular, the role played by barriers, pattern recognition systems, and microbial composition in early damage signaling requires further investigation. As such, this review highlights the innate immune response as a potential focus for research to better understand OM pathogenesis and development of interventions for patients treated with radiotherapy and chemotherapy. Future areas of evaluation include manipulation of microbial-mucosal interactions to alter cytotoxic sensitivity, use of germ-free models, and translation of innate immune-targeted agents interrogated for mucosal injury in other regions of the alimentary canal into OM-based clinical trials.

Keywords: inflammation; innate immunity; interventions; oral mucositis.

Figure 1

Role of the innate immune system in the development of OM. Initiation: Epithelial cells, connected via tight junctions, provide a physical barrier excluding oral microbes and their products from underlying tissue. Overlaying the epithelium is mucus and antimicrobial peptides, including IgA and tree-foil factors (TFF) secreted within saliva. At initiation of OM, the oral mucosa is exposed to radiotherapy or chemotherapy. Epithelial barrier breakdown: Following exposure, loss of tight junction proteins compromises epithelial barrier integrity. Salivary gland function and saliva composition is altered, decreasing its antimicrobial properties and influencing microbial and epithelial interactions. This induces compositional shifts in the oral microbiome, increasing the presence of pathobionts and enhancing IL-1β production by epithelial cells. Inflammation and ulceration: There is a loss of physical separation between surface microbes and the lamina propria, causing activation of oral mucosal innate immune cells, including macrophages, dendritic cells, neutrophils, and innate lymphoid cells, through interactions of PRRs (TLRs and NLRs) with PAMPs and DAMPs. OM progresses due to submucosal release of proinflammatory cytokines and chemokines, including TNFα, IL-1β, IL-6, CXCL8, and MIP. Healing: IL-17 plays an important role in fine-tuning neutrophil responses to trigger injury resolution and epithelium restoration.