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15 results on '"Brochu, Gaetan"'

9. NTPDase8 protects mice from intestinal inflammation by limiting P2Y6 receptor activation: identification of a new pathway of inflammation for the potential treatment of IBD

Author

Salem, Mabrouka, primary, Lecka, Joanna, additional, Pelletier, Julie, additional, Gomes Marconato, Danielle, additional, Dumas, Aline, additional, Vallières, Luc, additional, Brochu, Gaetan, additional, Robaye, Bernard, additional, Jobin, Christian, additional, and Sévigny, Jean, additional

Published
2021
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10. NTPDase8 protects mice from intestinal inflammation by limiting P2Y6 receptor activation: identification of a new pathway of inflammation for the potential treatment of IBD.

Author

Salem, Mabrouka, Lecka, Joanna, Pelletier, Julie, Marconato, Danielle Gomes, Dumas, Aline, Vallières, Luc, Brochu, Gaetan, Robaye, Bernard, Jobin, Christian, and Sévigny, Jean

Subjects
INTESTINAL diseases, INTESTINES, MACROPHAGE inflammatory proteins, HSP70 heat-shock proteins, POLYMYXIN B, REGULATORY T cells, INFLAMMATORY bowel diseases, MICE
Published
2022
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12. NTPDase8 protects mice from intestinal inflammation by limiting P2Y6receptor activation: identification of a new pathway of inflammation for the potential treatment of IBD

Author

Salem, Mabrouka, Lecka, Joanna, Pelletier, Julie, Gomes Marconato, Danielle, Dumas, Aline, Vallières, Luc, Brochu, Gaetan, Robaye, Bernard, Jobin, Christian, and Sévigny, Jean

Abstract

ObjectiveNucleotides are danger signals that activate inflammatory responses via binding P2 receptors. The nucleoside triphosphate diphosphohydrolase-8 (NTPDase8) is an ectonucleotidase that hydrolyses P2 receptor ligands. We investigated the role of NTPDase8 in intestinal inflammation.DesignWe generated NTPDase8-deficient (Entpd8–/–) mice to define the role of NTPDase8 in the dextran sodium sulfate (DSS) colitis model. To assess inflammation, colons were collected and analysed by histopathology, reverse transcriptase-quantitative real-time PCR (RT-qPCR) and immunohistochemistry. P2 receptor expression was analysed by RT-qPCR on primary intestinal epithelium and NTPDase8 activity by histochemistry. The role of intestinal P2Y6receptors was assessed by bone marrow transplantation experiments and with a P2Y6receptor antagonist.ResultsNTPDase8 is the dominant enzyme responsible for the hydrolysis of nucleotides in the lumen of the colon. Compared with wild-type (WT) control mice, the colon of Entpd8–/–mice treated with DSS displayed significantly more histological damage, immune cell infiltration, apoptosis and increased expression of several proinflammatory cytokines. P2Y6was the dominant P2Y receptor expressed at the mRNA level by the colonic epithelia. Irradiated P2ry6–/–mice transplanted with WT bone marrow were fully protected from DSS-induced intestinal inflammation. In agreement, the daily intrarectal injection of a P2Y6antagonist protected mice from DSS-induced intestinal inflammation in a dose-dependent manner. Finally, human intestinal epithelial cells express NTPDase8 and P2Y6similarly as in mice.ConclusionNTPDase8 protects the intestine from inflammation most probably by limiting the activation of P2Y6receptors in colonic epithelial cells. This may provide a novel therapeutic strategy for the treatment of inflammatory bowel disease.

Published
2022
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15. NTPDase8 protects mice from intestinal inflammation by limiting P2Y 6 receptor activation: identification of a new pathway of inflammation for the potential treatment of IBD.

Author

Salem M, Lecka J, Pelletier J, Gomes Marconato D, Dumas A, Vallières L, Brochu G, Robaye B, Jobin C, and Sévigny J

Subjects
Adenosine Triphosphatases genetics, Animals, Apoptosis, Bone Marrow Transplantation, Colon metabolism, Cytokines metabolism, Dextran Sulfate pharmacology, Disease Models, Animal, Epithelial Cells metabolism, Humans, Immunohistochemistry, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Mice, Inbred C57BL, Mice, Knockout, RNA, Messenger metabolism, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Thiourea pharmacology, Mice, Adenosine Triphosphatases metabolism, Colitis metabolism, Isothiocyanates pharmacology, Receptors, Purinergic P2 genetics, Receptors, Purinergic P2 metabolism, Thiourea analogs & derivatives
Abstract

Objective: Nucleotides are danger signals that activate inflammatory responses via binding P2 receptors. The nucleoside triphosphate diphosphohydrolase-8 (NTPDase8) is an ectonucleotidase that hydrolyses P2 receptor ligands. We investigated the role of NTPDase8 in intestinal inflammation., Design: We generated NTPDase8-deficient ( Entpd8 -/- ) mice to define the role of NTPDase8 in the dextran sodium sulfate (DSS) colitis model. To assess inflammation, colons were collected and analysed by histopathology, reverse transcriptase-quantitative real-time PCR (RT-qPCR) and immunohistochemistry. P2 receptor expression was analysed by RT-qPCR on primary intestinal epithelium and NTPDase8 activity by histochemistry. The role of intestinal P2Y 6 receptors was assessed by bone marrow transplantation experiments and with a P2Y 6 receptor antagonist., Results: NTPDase8 is the dominant enzyme responsible for the hydrolysis of nucleotides in the lumen of the colon. Compared with wild-type (WT) control mice, the colon of Entpd8 -/- mice treated with DSS displayed significantly more histological damage, immune cell infiltration, apoptosis and increased expression of several proinflammatory cytokines. P2Y 6 was the dominant P2Y receptor expressed at the mRNA level by the colonic epithelia. Irradiated P2ry6 -/- mice transplanted with WT bone marrow were fully protected from DSS-induced intestinal inflammation. In agreement, the daily intrarectal injection of a P2Y 6 antagonist protected mice from DSS-induced intestinal inflammation in a dose-dependent manner. Finally, human intestinal epithelial cells express NTPDase8 and P2Y 6 similarly as in mice., Conclusion: NTPDase8 protects the intestine from inflammation most probably by limiting the activation of P2Y 6 receptors in colonic epithelial cells. This may provide a novel therapeutic strategy for the treatment of inflammatory bowel disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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