Overexpression of ATP-activated P2X7 Receptors in the Intestinal Mucosa Is Implicated in the Pathogenesis of Crohnʼs Disease

Neves, Adriane R.; Castelo-Branco, Morgana T.; Figliuolo, Vanessa Ribeiro; Bernardazzi, Cláudio; Buongusto, Fernanda; Yoshimoto, Agnes N.; Nanini, Hayandra F.; Coutinho, Cláudia Mara Lara Melo; Carneiro, Antonio José V.; Coutinho‐Silva, Robson; Souza, Heitor Siffert Pereira de

doi:10.1097/01.mib.0000441201.10454.06

Cited by 88 publications

(82 citation statements)

References 73 publications

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“…Using a mouse model of acute AOM/DSS-induced colonic inflammation, we found that P2rx7 À/À mice displayed reduced signs of inflammation. This finding is in agreement with recent studies demonstrating that prophylactic systemic blockade of the P2RX7 activity prevented TNBS-induced colitis in rats (12) and that overexpression of P2RX7 in the intestinal mucosa was associated with the pathogenesis of CD (34). In the current study, we found that P2RX7 inactivation using selective antagonists as well as genetic deletion of the P2rx7 gene attenuated the weight loss and the overall disease activity score (Fig.…”

Section: Discussionsupporting

confidence: 93%

Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

et al. 2015

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Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD). Binding of extracellular ATP to the purinergic receptor P2RX7 has emerged as a critical event in controlling intestinal inflammation, acting to limit elevation of proinflammatory mast cells and cytokines and promote survival of regulatory T cells (Treg) and enteric neurons. In this study, we investigated the effect of P2RX7 blockade in an established mouse model of CAC. Using genetic and pharmacologic tools, we found unexpectedly that while P2RX7 mediated inflammatory responses, it also acted at an early time to suppress CAC development. P2RX7 blockade enhanced proliferation of intestinal epithelial cells and protected them from apoptosis. The proliferative effects of P2RX7 blockade were associated with an increased production of TGFb1 that was sufficient to stimulate the proliferation of intestinal epithelial cells. Finally, P2RX7 blockade also altered immune cell infiltration and promoted Treg accumulation within lesions of the digestive system. Taken together, our findings reveal an unexpected role for P2RX7 in preventing CAC, suggesting cautions in the use of P2RX7 inhibitors to treat IBD given the possibility of increasing risks CAC as a result. Cancer Res; 75(5); 835-45. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 93%

Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

et al. 2015

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“…In addition, recent findings suggest that commensal bacteria are the major source of eATP in the intestinal lumen. Furthermore, patients with CD have increased numbers of mucosa-associated adhesive E. coli [72]; direct purinergic communication between those bacteria and epithelial cells may lead to eATP-mediated mucosal inflammation. In the future, molecular imaging might be used to precisely elucidate the trafficking of ATP that is released into the luminal and mucosal inflammatory compartments in patients with IBD.…”

Section: Discussionmentioning

confidence: 99%

“…Collectively, these findings show that eATP disrupts the regulatory–inflammatory T-cell balance in the intestinal compartment and initiates intestinal inflammation. Data from both mouse and human studies suggest eATP/P2X7R pathways as promising therapeutic targets for overcoming IBD, and clinical trials for validation of therapeutic targets should be conducted in the future [72,73,74]. …”

Section: Eatp As An Inflammatory Mediator In Intestinal Inflammationmentioning

confidence: 99%

ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

Inami

Kiyono

Kurashima

2018

IJMS

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Extracellular nucleotides, such as adenosine triphosphate (ATP), are released from host cells including nerve termini, immune cells, injured or dead cells, and the commensal bacteria that reside in the gut lumen. Extracellular ATP interacts with the host through purinergic receptors, and promotes intercellular and bacteria-host communication to maintain the tissue homeostasis. However, the release of massive concentrations of ATP into extracellular compartments initiates acute and chronic inflammatory responses through the activation of immunocompetent cells (e.g., T cells, macrophages, and mast cells). In this review, we focus on the functions of ATP as a pathophysiologic mediator that is required for the induction and resolution of inflammation and inter-species communication.

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“…Regarding the signaling through purinergic receptors, the P2X7R was shown to play a role in the development of both innate and adaptive Th17 immune responses in skin and intestinal lamina propria (35,36,73). We previously showed that the purinergic signaling pathway was upregulated in VAT of MUO patients, and that it could chronically maintain the inflammasome activity and IL-1b production in tissue (43).…”

Section: Discussionmentioning

confidence: 99%

ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity

Pandolfi

Ferraro

Sananez

et al. 2016

The Journal of Immunology

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Obesity-induced inflammation is conducted by a metabolic pathway, which eventually causes activation of specialized immune cells and leads to an unresolved inflammatory response within the tissue. For this reason, it is critically important to determine how hypertrophic fat tissue alters T cell balance to drive inflammation. In this study, we identify the purinergic signaling as a novel mechanism driving the adaptive Th17 response in human visceral adipose tissue (VAT) of metabolically unhealthy obese patients. We demonstrate that ATP acting via the P2X7 receptor pathway promotes a Th17 polarizing microenvironment with high levels of IL-1β, IL-6, and IL-17 in VAT explants from lean donors. Moreover, in vitro blockade of the P2X7 receptor abrogates the levels of these cytokines. These findings are consistent with a greater frequency of Th17 cells in tissue from metabolically unhealthy obese donors, revealed not only by the presence of a baseline Th17-promoting milieu, but also by the higher expression of steadily recognized Th17 markers, such as RORC, IL-17 cytokine, and IL-23R, in comparison with metabolically healthy obese and lean donors. In addition, we demonstrate that CD39 expression on CD4+ effector T cells represents a novel Th17 marker in the inflamed VAT, which also confers protection against ATP-induced cell death. The manipulation of the purinergic signaling might represent a new therapeutic target to shift the CD4+ T cell balance under inflammatory conditions.

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Overexpression of ATP-activated P2X7 Receptors in the Intestinal Mucosa Is Implicated in the Pathogenesis of Crohnʼs Disease

Cited by 88 publications

References 73 publications

Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity

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