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An essential role of adenosine deaminase acting on RNA 1 in coeliac disease mucosa

BACKGROUND AND AIM: Type I interferons (IFNs) are highly expressed in the gut mucosa of celiac disease (CD) gut mucosa and stimulates immune response prompted by gluten ingestion, but the processes that maintain the production of these inflammatory molecules are not well understood. Adenosine deamin...

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Autores principales: Di Fusco, Davide, Segreto, Maria Teresa, Iannucci, Andrea, Maresca, Claudia, Franzè, Eleonora, Di Maggio, Giulia, Di Grazia, Antonio, Boccanera, Siro, Laudisi, Federica, Marafini, Irene, Paoluzi, Omero Alessandro, Michienzi, Alessandro, Monteleone, Giovanni, Monteleone, Ivan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200931/
https://www.ncbi.nlm.nih.gov/pubmed/37223095
http://dx.doi.org/10.3389/fimmu.2023.1175348
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author Di Fusco, Davide
Segreto, Maria Teresa
Iannucci, Andrea
Maresca, Claudia
Franzè, Eleonora
Di Maggio, Giulia
Di Grazia, Antonio
Boccanera, Siro
Laudisi, Federica
Marafini, Irene
Paoluzi, Omero Alessandro
Michienzi, Alessandro
Monteleone, Giovanni
Monteleone, Ivan
author_facet Di Fusco, Davide
Segreto, Maria Teresa
Iannucci, Andrea
Maresca, Claudia
Franzè, Eleonora
Di Maggio, Giulia
Di Grazia, Antonio
Boccanera, Siro
Laudisi, Federica
Marafini, Irene
Paoluzi, Omero Alessandro
Michienzi, Alessandro
Monteleone, Giovanni
Monteleone, Ivan
author_sort Di Fusco, Davide
collection PubMed
description BACKGROUND AND AIM: Type I interferons (IFNs) are highly expressed in the gut mucosa of celiac disease (CD) gut mucosa and stimulates immune response prompted by gluten ingestion, but the processes that maintain the production of these inflammatory molecules are not well understood. Adenosine deaminase acting on RNA 1 (ADAR1), an RNA-editing enzyme, plays a crucial role in inhibiting self or viral RNAs from activating auto-immune mediated responses, most notably within the type-I IFN production pathway. The aim of this study was to assess whether ADAR1 could contribute to the induction and/or progression of gut inflammation in patients with celiac disease. MATERIAL AND METHODS: ADAR1 expression was assessed by Real time PCR and Western blotting in duodenal biopsy taken from inactive and active celiac disease (CD) patients and normal controls (CTR). To analyze the role of ADAR1 in inflamed CD mucosa, lamina propria mononuclear cells (LPMC) were isolated from inactive CD and ADAR1 was silenced in with a specific antisense oligonucleotide (AS) and then incubated with a synthetic analogue of viral dsRNA (poly I:C). IFN-inducing pathways (IRF3, IRF7) in these cells were evaluated with Western blotting and inflammatory cytokines were evaluated with flow cytometry. Lastly, the role of ADAR1 was investigated in a mouse model of poly I:C-driven small intestine atrophy. RESULTS: Reduced ADAR1 expression was seen in duodenal biopsies compared to inactive CD and normal controls. Ex vivo organ cultures of duodenal mucosal biopsies, taken from inactive CD patients, stimulated with a peptic-tryptic digest of gliadin displayed a decreased expression of ADAR1. ADAR1 silencing in LPMC stimulated with a synthetic analogue of viral dsRNA strongly boosted the activation of IRF3 and IRF7 and the production of type-I IFN, TNF-α and IFN-γ. Administration of ADAR1 antisense but not sense oligonucleotide to mice with poly I:C-induced intestinal atrophy, significantly increased gut damage and inflammatory cytokines production. CONCLUSIONS: These data show that ADAR1 is an important regulator of intestinal immune homeostasis and demonstrate that defective ADAR1 expression could provide to amplifying pathogenic responses in CD intestinal mucosa.
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spelling pubmed-102009312023-05-23 An essential role of adenosine deaminase acting on RNA 1 in coeliac disease mucosa Di Fusco, Davide Segreto, Maria Teresa Iannucci, Andrea Maresca, Claudia Franzè, Eleonora Di Maggio, Giulia Di Grazia, Antonio Boccanera, Siro Laudisi, Federica Marafini, Irene Paoluzi, Omero Alessandro Michienzi, Alessandro Monteleone, Giovanni Monteleone, Ivan Front Immunol Immunology BACKGROUND AND AIM: Type I interferons (IFNs) are highly expressed in the gut mucosa of celiac disease (CD) gut mucosa and stimulates immune response prompted by gluten ingestion, but the processes that maintain the production of these inflammatory molecules are not well understood. Adenosine deaminase acting on RNA 1 (ADAR1), an RNA-editing enzyme, plays a crucial role in inhibiting self or viral RNAs from activating auto-immune mediated responses, most notably within the type-I IFN production pathway. The aim of this study was to assess whether ADAR1 could contribute to the induction and/or progression of gut inflammation in patients with celiac disease. MATERIAL AND METHODS: ADAR1 expression was assessed by Real time PCR and Western blotting in duodenal biopsy taken from inactive and active celiac disease (CD) patients and normal controls (CTR). To analyze the role of ADAR1 in inflamed CD mucosa, lamina propria mononuclear cells (LPMC) were isolated from inactive CD and ADAR1 was silenced in with a specific antisense oligonucleotide (AS) and then incubated with a synthetic analogue of viral dsRNA (poly I:C). IFN-inducing pathways (IRF3, IRF7) in these cells were evaluated with Western blotting and inflammatory cytokines were evaluated with flow cytometry. Lastly, the role of ADAR1 was investigated in a mouse model of poly I:C-driven small intestine atrophy. RESULTS: Reduced ADAR1 expression was seen in duodenal biopsies compared to inactive CD and normal controls. Ex vivo organ cultures of duodenal mucosal biopsies, taken from inactive CD patients, stimulated with a peptic-tryptic digest of gliadin displayed a decreased expression of ADAR1. ADAR1 silencing in LPMC stimulated with a synthetic analogue of viral dsRNA strongly boosted the activation of IRF3 and IRF7 and the production of type-I IFN, TNF-α and IFN-γ. Administration of ADAR1 antisense but not sense oligonucleotide to mice with poly I:C-induced intestinal atrophy, significantly increased gut damage and inflammatory cytokines production. CONCLUSIONS: These data show that ADAR1 is an important regulator of intestinal immune homeostasis and demonstrate that defective ADAR1 expression could provide to amplifying pathogenic responses in CD intestinal mucosa. Frontiers Media S.A. 2023-05-08 /pmc/articles/PMC10200931/ /pubmed/37223095 http://dx.doi.org/10.3389/fimmu.2023.1175348 Text en Copyright © 2023 Di Fusco, Segreto, Iannucci, Maresca, Franzè, Di Maggio, Di Grazia, Boccanera, Laudisi, Marafini, Paoluzi, Michienzi, Monteleone and Monteleone 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
Di Fusco, Davide
Segreto, Maria Teresa
Iannucci, Andrea
Maresca, Claudia
Franzè, Eleonora
Di Maggio, Giulia
Di Grazia, Antonio
Boccanera, Siro
Laudisi, Federica
Marafini, Irene
Paoluzi, Omero Alessandro
Michienzi, Alessandro
Monteleone, Giovanni
Monteleone, Ivan
An essential role of adenosine deaminase acting on RNA 1 in coeliac disease mucosa
title An essential role of adenosine deaminase acting on RNA 1 in coeliac disease mucosa
title_full An essential role of adenosine deaminase acting on RNA 1 in coeliac disease mucosa
title_fullStr An essential role of adenosine deaminase acting on RNA 1 in coeliac disease mucosa
title_full_unstemmed An essential role of adenosine deaminase acting on RNA 1 in coeliac disease mucosa
title_short An essential role of adenosine deaminase acting on RNA 1 in coeliac disease mucosa
title_sort essential role of adenosine deaminase acting on rna 1 in coeliac disease mucosa
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200931/
https://www.ncbi.nlm.nih.gov/pubmed/37223095
http://dx.doi.org/10.3389/fimmu.2023.1175348
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