The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome
<b>Background:</b> Given the role of the P2X7 receptor (P2X7R) in inflammatory bowel diseases (IBD), we investigated its role in the development and progression of colitis-associated colorectal cancer (CA-CRC). <b>Methods:</b> CA-CRC was induced in P2X7R<sup>+/+</sup...
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| Format: | Article |
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/9/4616 |
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| author | Claudio Bernardazzi Morgana Teixeira Lima Castelo-Branco Beatriz Pêgo Beatriz Elias Ribeiro Siane Lopes Bittencourt Rosas Patrícia Teixeira Santana João Carlos Machado Camille Leal Fabiano Thompson Robson Coutinho-Silva Heitor Siffert Pereira de Souza |
| author_facet | Claudio Bernardazzi Morgana Teixeira Lima Castelo-Branco Beatriz Pêgo Beatriz Elias Ribeiro Siane Lopes Bittencourt Rosas Patrícia Teixeira Santana João Carlos Machado Camille Leal Fabiano Thompson Robson Coutinho-Silva Heitor Siffert Pereira de Souza |
| author_sort | Claudio Bernardazzi |
| collection | DOAJ |
| description | <b>Background:</b> Given the role of the P2X7 receptor (P2X7R) in inflammatory bowel diseases (IBD), we investigated its role in the development and progression of colitis-associated colorectal cancer (CA-CRC). <b>Methods:</b> CA-CRC was induced in P2X7R<sup>+/+</sup> and P2X7R<sup>−/−</sup> mice with azoxymethane (AOM) combined with dextran sodium sulfate (DSS). In a therapeutic protocol, P2X7R<sup>+/+</sup> mice were treated with a P2X7R-selective inhibitor (A740003). Mice were evaluated with follow-up video endoscopy with endoluminal ultrasound biomicroscopy. Colon tissue was analyzed for histological changes, densities of immune cells, expression of transcription factors, cytokines, genes, DNA methylation, and microbiome composition of fecal samples by sequencing for 16S rRNA. <b>Results:</b> The P2X7R<sup>+/+</sup> mice displayed more ulcers, tumors, and greater wall thickness, than the P2X7R<sup>−/−</sup> and the P2X7R<sup>+/+</sup> mice treated with A740003. The P2X7R<sup>+/+</sup> mice showed increased accumulation of immune cells, production of proinflammatory cytokines, activation of intracellular signaling pathways, and upregulation of <i>NLRP3</i> and <i>NLRP12</i> genes, stabilized after the P2X7R-blockade. Microbial changes were observed in the P2X7R<sup>−/−</sup> and P2X7R<sup>+/+</sup>-induced mice, partially reversed by the A740003 treatment. <b>Conclusions:</b> Regulatory mechanisms activated downstream of the P2X7R in combination with signals from a dysbiotic microbiota result in the activation of intracellular signaling pathways and the inflammasome, amplifying the inflammatory response and promoting CA-CRC development. |
| first_indexed | 2024-03-10T04:07:29Z |
| format | Article |
| id | doaj.art-a8aca7c6ceb5459c8b10951499c124db |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:07:29Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a8aca7c6ceb5459c8b10951499c124db2023-11-23T08:19:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01239461610.3390/ijms23094616The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the InflammasomeClaudio Bernardazzi0Morgana Teixeira Lima Castelo-Branco1Beatriz Pêgo2Beatriz Elias Ribeiro3Siane Lopes Bittencourt Rosas4Patrícia Teixeira Santana5João Carlos Machado6Camille Leal7Fabiano Thompson8Robson Coutinho-Silva9Heitor Siffert Pereira de Souza10Department of Pediatrics, University of Arizona, Tucson, AZ 85724, USADepartment of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, BrazilDepartment of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, BrazilDepartment of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, BrazilDepartment of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, BrazilDepartment of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, BrazilBiomedical Engineering Program, COPPE, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, BrazilInstitute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-599, BrazilInstitute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-599, BrazilInstitute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, BrazilDepartment of Clinical Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil<b>Background:</b> Given the role of the P2X7 receptor (P2X7R) in inflammatory bowel diseases (IBD), we investigated its role in the development and progression of colitis-associated colorectal cancer (CA-CRC). <b>Methods:</b> CA-CRC was induced in P2X7R<sup>+/+</sup> and P2X7R<sup>−/−</sup> mice with azoxymethane (AOM) combined with dextran sodium sulfate (DSS). In a therapeutic protocol, P2X7R<sup>+/+</sup> mice were treated with a P2X7R-selective inhibitor (A740003). Mice were evaluated with follow-up video endoscopy with endoluminal ultrasound biomicroscopy. Colon tissue was analyzed for histological changes, densities of immune cells, expression of transcription factors, cytokines, genes, DNA methylation, and microbiome composition of fecal samples by sequencing for 16S rRNA. <b>Results:</b> The P2X7R<sup>+/+</sup> mice displayed more ulcers, tumors, and greater wall thickness, than the P2X7R<sup>−/−</sup> and the P2X7R<sup>+/+</sup> mice treated with A740003. The P2X7R<sup>+/+</sup> mice showed increased accumulation of immune cells, production of proinflammatory cytokines, activation of intracellular signaling pathways, and upregulation of <i>NLRP3</i> and <i>NLRP12</i> genes, stabilized after the P2X7R-blockade. Microbial changes were observed in the P2X7R<sup>−/−</sup> and P2X7R<sup>+/+</sup>-induced mice, partially reversed by the A740003 treatment. <b>Conclusions:</b> Regulatory mechanisms activated downstream of the P2X7R in combination with signals from a dysbiotic microbiota result in the activation of intracellular signaling pathways and the inflammasome, amplifying the inflammatory response and promoting CA-CRC development.https://www.mdpi.com/1422-0067/23/9/4616colitis-associated colorectal cancergut microbiotainflammatory bowel diseaseP2X7Rpurinergic signaling |
| spellingShingle | Claudio Bernardazzi Morgana Teixeira Lima Castelo-Branco Beatriz Pêgo Beatriz Elias Ribeiro Siane Lopes Bittencourt Rosas Patrícia Teixeira Santana João Carlos Machado Camille Leal Fabiano Thompson Robson Coutinho-Silva Heitor Siffert Pereira de Souza The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome International Journal of Molecular Sciences colitis-associated colorectal cancer gut microbiota inflammatory bowel disease P2X7R purinergic signaling |
| title | The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome |
| title_full | The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome |
| title_fullStr | The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome |
| title_full_unstemmed | The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome |
| title_short | The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome |
| title_sort | p2x7 receptor promotes colorectal inflammation and tumorigenesis by modulating gut microbiota and the inflammasome |
| topic | colitis-associated colorectal cancer gut microbiota inflammatory bowel disease P2X7R purinergic signaling |
| url | https://www.mdpi.com/1422-0067/23/9/4616 |
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