Colitis susceptibility in mice with reactive oxygen species deficiency is mediated by mucus barrier and immune defense defects

Gabriella Aviello, Ashish K. Singh, Sharon O’Neill, Emer Conroy, William Gallagher, Giuseppe D’Agostino, Alan W. Walker, Billy Bourke, Dimitri Scholz, Ulla G. Knaus (Corresponding Author)

Research output: Contribution to journalArticle

Abstract

Reactive oxygen species (ROS) generated by NADPH oxidases (NOX/DUOX) provide antimicrobial defense, redox signaling, and gut barrier maintenance. Inactivating NOX variants are associated with comorbid intestinal inflammation in chronic granulomatous disease (CGD; NOX2) and pediatric inflammatory bowel disease (IBD; NOX1); however Nox-deficient mice do not reflect human disease susceptibility. Here we assessed if a hypomorphic patient-relevant CGD mutation will increase the risk for intestinal inflammation in mice. Cyba (p22phox) mutant mice generated low intestinal ROS, while maintaining Nox4 function. The Cyba variant caused profound mucus layer disruption with bacterial penetration into crypts, dysbiosis, and a compromised innate immune response to invading microbes, leading to mortality. Approaches used in treatment-resistant CGD or pediatric IBD such as bone marrow transplantation or oral antibiotic treatment ameliorated or prevented disease in mice. The Cyba mutant mouse phenotype implicates loss of both mucus barrier and efficient innate immune defense in the pathogenesis of intestinal inflammation due to ROS deficiency, supporting a combined-hit model where a single disease variant compromises different cellular functions in interdependent compartments.
Original languageEnglish
JournalMucosal Immunology
Early online date25 Sep 2019
DOIs
Publication statusE-pub ahead of print - 25 Sep 2019

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Colitis
Mucus
Reactive Oxygen Species
Inflammation
Dysbiosis
Pediatrics
Chronic Granulomatous Disease
NADPH Oxidase
Disease Susceptibility
Bone Marrow Transplantation
Inflammatory Bowel Diseases
Innate Immunity
Oxidation-Reduction
Maintenance
Hypoxia
Anti-Bacterial Agents
Phenotype
Mutation
Mortality
Therapeutics

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Colitis susceptibility in mice with reactive oxygen species deficiency is mediated by mucus barrier and immune defense defects. / Aviello, Gabriella; Singh, Ashish K.; O’Neill, Sharon; Conroy, Emer; Gallagher, William; D’Agostino, Giuseppe; Walker, Alan W.; Bourke, Billy; Scholz, Dimitri; Knaus, Ulla G. (Corresponding Author).

In: Mucosal Immunology, 25.09.2019.

Research output: Contribution to journalArticle

Aviello, Gabriella ; Singh, Ashish K. ; O’Neill, Sharon ; Conroy, Emer ; Gallagher, William ; D’Agostino, Giuseppe ; Walker, Alan W. ; Bourke, Billy ; Scholz, Dimitri ; Knaus, Ulla G. / Colitis susceptibility in mice with reactive oxygen species deficiency is mediated by mucus barrier and immune defense defects. In: Mucosal Immunology. 2019.
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abstract = "Reactive oxygen species (ROS) generated by NADPH oxidases (NOX/DUOX) provide antimicrobial defense, redox signaling, and gut barrier maintenance. Inactivating NOX variants are associated with comorbid intestinal inflammation in chronic granulomatous disease (CGD; NOX2) and pediatric inflammatory bowel disease (IBD; NOX1); however Nox-deficient mice do not reflect human disease susceptibility. Here we assessed if a hypomorphic patient-relevant CGD mutation will increase the risk for intestinal inflammation in mice. Cyba (p22phox) mutant mice generated low intestinal ROS, while maintaining Nox4 function. The Cyba variant caused profound mucus layer disruption with bacterial penetration into crypts, dysbiosis, and a compromised innate immune response to invading microbes, leading to mortality. Approaches used in treatment-resistant CGD or pediatric IBD such as bone marrow transplantation or oral antibiotic treatment ameliorated or prevented disease in mice. The Cyba mutant mouse phenotype implicates loss of both mucus barrier and efficient innate immune defense in the pathogenesis of intestinal inflammation due to ROS deficiency, supporting a combined-hit model where a single disease variant compromises different cellular functions in interdependent compartments.",
author = "Gabriella Aviello and Singh, {Ashish K.} and Sharon O’Neill and Emer Conroy and William Gallagher and Giuseppe D’Agostino and Walker, {Alan W.} and Billy Bourke and Dimitri Scholz and Knaus, {Ulla G.}",
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N1 - Acknowledgements The authors thank Sophie Shaw, CGEBM Aberdeen, for assistance with ENA submission. The work was supported by Science Foundation Ireland (U.G.K.), the National Children’s Research Center (U.G.K. and B.B.), the European Crohn’s and Colitis Organization (G.A.), the Medical Research Council MC/PC/15077 (G.A.) and MR/P009824/1 (G.D.), and the Scottish Government’s Rural and Environment Science and Analytical Services division (A.W.W.). The authors would also like to acknowledge the support of the Maxwell compute cluster funded by the University of Aberdeen.

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N2 - Reactive oxygen species (ROS) generated by NADPH oxidases (NOX/DUOX) provide antimicrobial defense, redox signaling, and gut barrier maintenance. Inactivating NOX variants are associated with comorbid intestinal inflammation in chronic granulomatous disease (CGD; NOX2) and pediatric inflammatory bowel disease (IBD; NOX1); however Nox-deficient mice do not reflect human disease susceptibility. Here we assessed if a hypomorphic patient-relevant CGD mutation will increase the risk for intestinal inflammation in mice. Cyba (p22phox) mutant mice generated low intestinal ROS, while maintaining Nox4 function. The Cyba variant caused profound mucus layer disruption with bacterial penetration into crypts, dysbiosis, and a compromised innate immune response to invading microbes, leading to mortality. Approaches used in treatment-resistant CGD or pediatric IBD such as bone marrow transplantation or oral antibiotic treatment ameliorated or prevented disease in mice. The Cyba mutant mouse phenotype implicates loss of both mucus barrier and efficient innate immune defense in the pathogenesis of intestinal inflammation due to ROS deficiency, supporting a combined-hit model where a single disease variant compromises different cellular functions in interdependent compartments.

AB - Reactive oxygen species (ROS) generated by NADPH oxidases (NOX/DUOX) provide antimicrobial defense, redox signaling, and gut barrier maintenance. Inactivating NOX variants are associated with comorbid intestinal inflammation in chronic granulomatous disease (CGD; NOX2) and pediatric inflammatory bowel disease (IBD; NOX1); however Nox-deficient mice do not reflect human disease susceptibility. Here we assessed if a hypomorphic patient-relevant CGD mutation will increase the risk for intestinal inflammation in mice. Cyba (p22phox) mutant mice generated low intestinal ROS, while maintaining Nox4 function. The Cyba variant caused profound mucus layer disruption with bacterial penetration into crypts, dysbiosis, and a compromised innate immune response to invading microbes, leading to mortality. Approaches used in treatment-resistant CGD or pediatric IBD such as bone marrow transplantation or oral antibiotic treatment ameliorated or prevented disease in mice. The Cyba mutant mouse phenotype implicates loss of both mucus barrier and efficient innate immune defense in the pathogenesis of intestinal inflammation due to ROS deficiency, supporting a combined-hit model where a single disease variant compromises different cellular functions in interdependent compartments.

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