Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248500/ https://www.ncbi.nlm.nih.gov/pubmed/34220843 http://dx.doi.org/10.3389/fimmu.2021.687627 |
_version_ | 1783716737180499968 |
---|---|
author | Saul-McBeth, Jessica Dillon, John Lee, Aaron Launder, Dylan Kratch, Jacqueline M. Abutaha, Eanas Williamson, Alexandria A. Schroering, Allen G. Michalski, Grace Biswas, Priosmita Conti, Samuel R. Shetty, Amol C. McCracken, Carrie Bruno, Vincent M. Parsai, E. Ishmael Conti, Heather R. |
author_facet | Saul-McBeth, Jessica Dillon, John Lee, Aaron Launder, Dylan Kratch, Jacqueline M. Abutaha, Eanas Williamson, Alexandria A. Schroering, Allen G. Michalski, Grace Biswas, Priosmita Conti, Samuel R. Shetty, Amol C. McCracken, Carrie Bruno, Vincent M. Parsai, E. Ishmael Conti, Heather R. |
author_sort | Saul-McBeth, Jessica |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-8248500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82485002021-07-02 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 M. Abutaha, Eanas Williamson, Alexandria A. Schroering, Allen G. Michalski, Grace Biswas, Priosmita Conti, Samuel R. Shetty, Amol C. McCracken, Carrie Bruno, Vincent M. Parsai, E. Ishmael Conti, Heather R. Front Immunol Immunology 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. Frontiers Media S.A. 2021-06-17 /pmc/articles/PMC8248500/ /pubmed/34220843 http://dx.doi.org/10.3389/fimmu.2021.687627 Text en Copyright © 2021 Saul-McBeth, Dillon, Lee, Launder, Kratch, Abutaha, Williamson, Schroering, Michalski, Biswas, Conti, Shetty, McCracken, Bruno, Parsai and Conti https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Saul-McBeth, Jessica Dillon, John Lee, Aaron Launder, Dylan Kratch, Jacqueline M. Abutaha, Eanas Williamson, Alexandria A. Schroering, Allen G. Michalski, Grace Biswas, Priosmita Conti, Samuel R. Shetty, Amol C. McCracken, Carrie Bruno, Vincent M. Parsai, E. Ishmael Conti, Heather R. Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling |
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 | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248500/ https://www.ncbi.nlm.nih.gov/pubmed/34220843 http://dx.doi.org/10.3389/fimmu.2021.687627 |
work_keys_str_mv | AT saulmcbethjessica tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT dillonjohn tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT leeaaron tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT launderdylan tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT kratchjacquelinem tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT abutahaeanas tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT williamsonalexandriaa tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT schroeringalleng tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT michalskigrace tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT biswaspriosmita tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT contisamuelr tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT shettyamolc tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT mccrackencarrie tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT brunovincentm tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT parsaieishmael tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling AT contiheatherr tissuedamageinradiationinducedoralmucositisismitigatedbyil17receptorsignaling |