Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling
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 lim...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.687627/full |
| _version_ | 1823938573260292096 |
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| author | Jessica Saul-McBeth John Dillon Aaron Lee Dylan Launder Jacqueline M. Kratch Eanas Abutaha Alexandria A. Williamson Allen G. Schroering Grace Michalski Priosmita Biswas Samuel R. Conti Amol C. Shetty Carrie McCracken Vincent M. Bruno E. Ishmael Parsai Heather R. Conti |
| author_facet | Jessica Saul-McBeth John Dillon Aaron Lee Dylan Launder Jacqueline M. Kratch Eanas Abutaha Alexandria A. Williamson Allen G. Schroering Grace Michalski Priosmita Biswas Samuel R. Conti Amol C. Shetty Carrie McCracken Vincent M. Bruno E. Ishmael Parsai Heather R. Conti |
| author_sort | Jessica Saul-McBeth |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T02:47:24Z |
| format | Article |
| id | doaj.art-7130fdda36ae4b158f008da3601ae03e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T02:47:24Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-7130fdda36ae4b158f008da3601ae03e2022-12-21T22:06:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-06-011210.3389/fimmu.2021.687627687627Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor SignalingJessica Saul-McBeth0John Dillon1Aaron Lee2Dylan Launder3Jacqueline M. Kratch4Eanas Abutaha5Alexandria A. Williamson6Allen G. Schroering7Grace Michalski8Priosmita Biswas9Samuel R. Conti10Amol C. Shetty11Carrie McCracken12Vincent M. Bruno13E. Ishmael Parsai14Heather R. Conti15Department of Biological Sciences, University of Toledo, Toledo, OH, United StatesDepartment of Biological Sciences, University of Toledo, Toledo, OH, United StatesDepartment of Radiation Oncology, Division of Medical Physics, The University of Toledo, Toledo, OH, United StatesDepartment of Biological Sciences, University of Toledo, Toledo, OH, United StatesDepartment of Biological Sciences, University of Toledo, Toledo, OH, United StatesDepartment of Biological Sciences, University of Toledo, Toledo, OH, United StatesDepartment of Biological Sciences, University of Toledo, Toledo, OH, United StatesDepartment of Surgery, The University of Toledo, Toledo, OH, United StatesDepartment of Biological Sciences, University of Toledo, Toledo, OH, United StatesDepartment of Biological Sciences, University of Toledo, Toledo, OH, United StatesDepartment of Biological Sciences, University of Toledo, Toledo, OH, United StatesInstitute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United StatesInstitute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United StatesInstitute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United StatesDepartment of Radiation Oncology, Division of Medical Physics, The University of Toledo, Toledo, OH, United StatesDepartment of Biological Sciences, University of Toledo, Toledo, OH, United StatesOral 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.687627/fulloral mucositis (OM)inflammationinterleukin-17oral mucosahealing |
| spellingShingle | Jessica Saul-McBeth John Dillon Aaron Lee Dylan Launder Jacqueline M. Kratch Eanas Abutaha Alexandria A. Williamson Allen G. Schroering Grace Michalski Priosmita Biswas Samuel R. Conti Amol C. Shetty Carrie McCracken Vincent M. Bruno E. Ishmael Parsai Heather R. Conti Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling Frontiers in Immunology oral mucositis (OM) inflammation interleukin-17 oral mucosa healing |
| title | Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling |
| title_full | Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling |
| title_fullStr | Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling |
| title_full_unstemmed | Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling |
| title_short | Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling |
| title_sort | tissue damage in radiation induced oral mucositis is mitigated by il 17 receptor signaling |
| topic | oral mucositis (OM) inflammation interleukin-17 oral mucosa healing |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.687627/full |
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