Synergistic exacerbation of oral mucositis caused by IL-23 deficiency and oral exposure.

Targeted head and neck irradiation (HNI) used for cancer therapy causes mucosal damage and immune dysregulation, leaving cancer patients highly susceptible to infections of the oral mucosa. Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by , a commensal fungus found in up to 80% of the population at any given time. High colonization levels of are known to worsen damage caused by HNI. The interleukin-23 (IL-23)-T-helper 17 (Th17) axis is a central and non-redundant mediator of immunity to OPC, and anti-cytokine biologics targeting IL-23 have come into widespread clinical use for treating various autoimmune conditions. Here, we sought to understand the consequences of IL-23 deficiency in the setting of HNI, taking advantage of a mouse model of radiation-induced oral mucositis (OM) which we combined with fungal infection. Surprisingly, mice lacking IL-23 did not show increased signs of injury to the oral mucosa when subjected to HNI. However, in mice subjected to HNI and exposed to oral , damage to the oral mucosa was markedly exacerbated, accompanied by substantially increased fungal susceptibility when IL-23 was absent. Thus, IL-23-driven control of fungal infections is needed to mitigate susceptibility to OM in the high proportion of individuals who carry in the mouth.IMPORTANCEIL-23 plays key roles in expanding the T-helper 17 (Th17) cell subset during differentiation and promoting expression of cytokines, including the subset-defining cytokine IL-17 (IL-17A). While the effector cytokines produced by Th17 cells are required for host defense against extracellular microbes, especially , these can also be pathogenic during inflammatory and autoimmune disorders including psoriasis, psoriatic arthritis, and ankylosing spondylitis, among others. While IL-23 and IL-17 are similarly required for protection against oropharyngeal candidiasis (OPC), they can exert divergent functions in other forms of immune-mediated inflammation; for example, anti-IL-17 blockade or gene deficiency is linked to inflammatory bowel disease, whereas loss of IL-23 is protective in this setting. We previously showed that head and neck irradiation (HNI) induces IL-17 expression in oral tissue and that IL-17 receptor (IL-17R) signaling is required for resistance against mucosal damage and OPC. In contrast, we show here that loss of IL-23 does not affect oral mucosal injury caused by HNI. However, lack of IL-23 magnifies HNI-induced susceptibility to OPC due to insufficient levels of antimicrobial peptides. Clinically, these findings suggest that patients receiving treatments that target IL-23 may not need to discontinue therapy should they require HNI, but that screening for oral may be useful to help limit the risk of developing severe OM and its attendant adverse events.