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

Saul-McBeth, Jessica; Dillon, John; Lee, Aaron; Launder, Dylan; Kratch, Jacqueline; Abutaha, Eanas; Williamson, Alexandria A.; Schroering, Allen; Michalski, Grace; Biswas, Priosmita; Conti, Samuel R. Iii; Shetty, Amol; McCracken, Carrie; Bruno, Vincent M.; Parsai, E; Conti, Heather R.

doi:10.3389/fimmu.2021.687627

Cited by 13 publications

(28 citation statements)

References 71 publications

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“…Mice were exposed to HNI as previously described in [ 28 ]. Briefly, mice were immobilized using an anesthesia protocol approved by the Department of Laboratory Animal Research at the University of Toledo.…”

Section: Methodsmentioning

confidence: 99%

“…Tongues were rinsed with PBS and stained with 1% toluidine blue for 2 min, followed by washing with acetic acid for 30 s to reveal ulcerative lesions as previously described [ 28 ]. The percentage of toluidine blue-positive areas were calculated using ImageJ software and % damage quantified by the area of toluidine blue positive area/surface area of whole tongue *100.…”

Section: Methodsmentioning

confidence: 99%

“…It is generally thought that a strong neutrophil response is pathogenic in VVC, regardless of whether recruitment is IL-17-driven or not [ 26 , 27 ]. Since radiation exposure leads to a large number of neutrophils in the oral tissue during IL-17RA deficiency, it was important to determine the phenotype of these neutrophils during OPC associated with radiation damage [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…Oral mucositis (OM) can be a severe complication of HNI, associated with unmanageable pain and a high financial burden that oftentimes can lead to the patient discontinuing treatment for the malignancy [ 3 , 31 ]. Radiation exposure to the head and neck regions of mice induces IL-17 expression in the oral mucosa, with the highest levels of the cytokine detected during peak OM damage [ 28 ]. Il17ra −/− mice exposed to HNI suffer excessive OM damage because IL-17 supports oral epithelial regeneration and regulates the neutrophil response, whereas, in the absence of IL-17RA, other cytokines including IL-1 are dysregulated, leading to increased neutrophilic infiltration and inflammatory damage [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…Radiation exposure to the head and neck regions of mice induces IL-17 expression in the oral mucosa, with the highest levels of the cytokine detected during peak OM damage [ 28 ]. Il17ra −/− mice exposed to HNI suffer excessive OM damage because IL-17 supports oral epithelial regeneration and regulates the neutrophil response, whereas, in the absence of IL-17RA, other cytokines including IL-1 are dysregulated, leading to increased neutrophilic infiltration and inflammatory damage [ 28 ]. As noted above, various patient populations are susceptible to oral Candida infections, yet it is not fully understood how different forms of immunosuppression affect Th17-related immunity directly [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Radiation Exposure Perturbs IL-17RA-Mediated Immunity Leading to Changes in Neutrophil Responses That Increase Susceptibility to Oropharyngeal Candidiasis

Saul-McBeth

Dillon

Launder

et al. 2022

JoF

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Fungal infections caused by Candida albicans are a serious problem for immunocompromised individuals, including those undergoing radiotherapy for head and neck cancers. Targeted irradiation causes inflammatory dysregulation and damage to the oral mucosa that can be exacerbated by candidiasis. Post-irradiation the cytokine interleukin-17 (IL-17) protects the oral mucosae by promoting oral epithelial regeneration and balancing the oral immune cell populations, which leads to the eventual healing of the tissue. IL-17 signaling is also critical for the antifungal response during oropharyngeal candidiasis (OPC). Yet, the benefit of IL-17 during other forms of candidiasis, such as vulvovaginal candidiasis, is not straightforward. Therefore, it was important to determine the role of IL-17 during OPC associated with radiation-induced inflammatory damage. To answer this question, we exposed Il17ra−/− and wild-type mice to head-neck irradiation (HNI) and OPC to determine if the IL-17 signaling pathway was still protective against C. albicans. HNI increased susceptibility to OPC, and in Il17ra−/− mice, the mucosal damage and fungal burden were elevated compared to control mice. Intriguingly, neutrophil influx was increased in Il17ra−/− mice, yet these cells had reduced capacity to phagocytose C. albicans and failed to clear OPC compared to immunocompetent mice. These findings suggest that radiotherapy not only causes physical damage to the oral cavity but also skews immune mediators, leading to increased susceptibility to oropharyngeal candidiasis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Radiation Exposure Perturbs IL-17RA-Mediated Immunity Leading to Changes in Neutrophil Responses That Increase Susceptibility to Oropharyngeal Candidiasis

Saul-McBeth

Dillon

Launder

et al. 2022

JoF

Self Cite

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Recombinant Human Keratinocyte Growth Factor Ameliorates Cancer Treatment‐Induced Oral Mucositis on a Chip

Ly,

Rajtboriraks,

Elgerbi

et al. 2024

Adv Healthcare Materials

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Oral mucositis (OM) is a severe complication of cancer therapies caused by off‐target cytotoxicity. Palifermin, which is recombinant human keratinocyte growth factor (KGF), is currently the only mitigating treatment available to a subset of OM patients. Determining the cell and molecular mechanisms of cancer treatment‐induced OM and the anti‐mucositis effects of KGF will aid in identifying effective future treatments. This study evaluates a previously developed oral mucositis on a chip (OM‐OC) as a screening platform for anti‐mucositis treatments, using KGF as a well‐studied example. The OM‐OC model comprises a confluent keratinocyte layer attached to a basement membrane‐lined subepithelial layer consisting of fibroblasts and endothelial cells in a stable collagen gel. Mucositis effects were induced by cisplatin, radiation, and combined treatment followed by a recovery period. Cell damage, barrier dysfunction, and molecular expression during OM induction and resolution were assessed via widefield microscopy, viability and toxicity assays, and antibody arrays. Cell and molecular responses were identified during OM induction and resolution with and without KGF treatment at 1–10 ng/mL, consistent with acute damage followed by repair partially enhanced by KGF, and suggest that KGF treatment in vitro does not return levels of some pro‐inflammatory cytokines to baseline.This article is protected by copyright. All rights reserved

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A preclinical model to investigate normal tissue damage following fractionated radiotherapy to the head and neck

Juvkam

Zlygosteva

Arous

et al. 2022

Journal of Radiation Research

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Radiotherapy (RT) of head and neck (H&N) cancer is known to cause both early- and late-occurring toxicities. To better appraise normal tissue responses and their dependence on treatment parameters such as radiation field and type, as well as dose and fractionation scheme, a preclinical model with relevant endpoints is required. 12-week old female C57BL/6 J mice were irradiated with 100 or 180 kV X-rays to total doses ranging from 30 to 85 Gy, given in 10 fractions over 5 days. The radiation field covered the oral cavity, swallowing structures and salivary glands. Monte Carlo simulations were employed to estimate tissue dose distribution. The follow-up period was 35 days, in order to study the early radiation-induced effects. Baseline and post irradiation investigations included macroscopic and microscopic examinations of the skin, lips, salivary glands and oral mucosa. Saliva sampling was performed to assess the salivary gland function following radiation exposure. A dose dependent radiation dermatitis in the skin was observed for doses above 30 Gy. Oral mucositis in the tongue appeared as ulcerations on the ventral surface of the tongue for doses of 75–85 Gy. The irradiated mice showed significantly reduced saliva production compared to controls. In summary, a preclinical model to investigate a broad panel of normal tissue responses following fractionated irradiation of the H&N region was established. The optimal dose to study early radiation-induced effects was found to be around 75 Gy, as this was the highest tolerated dose that gave acute effects similar to that observed in cancer patients.

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

Cited by 13 publications

References 71 publications

Radiation Exposure Perturbs IL-17RA-Mediated Immunity Leading to Changes in Neutrophil Responses That Increase Susceptibility to Oropharyngeal Candidiasis

Radiation Exposure Perturbs IL-17RA-Mediated Immunity Leading to Changes in Neutrophil Responses That Increase Susceptibility to Oropharyngeal Candidiasis

Recombinant Human Keratinocyte Growth Factor Ameliorates Cancer Treatment‐Induced Oral Mucositis on a Chip

A preclinical model to investigate normal tissue damage following fractionated radiotherapy to the head and neck

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