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

Hofman, Paul; Cherfils‐Vicini, Julien; Bazin, Marie; Ilié, Marius; Juhel, Thierry; Hébuterne, Xavier; Gilson, Éric; Schmid-Alliana, Annie; Boyer, Olivier; Adriouch, Sahil; Vouret‐Craviari, Valérie

doi:10.1158/0008-5472.can-14-1778

Cited by 107 publications

(115 citation statements)

References 49 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…Understanding the complex and sequential molecular mechanisms by which macrophages are recruited to the intestines in response to bacteria remains an important goal to treat gut-origin sepsis. Additionally, the administration of P2X7R inhibitors suggests caution given the possibility of increasing the risk of tumor growth 41, 42 . The present study did not investigate the possible effects of P2X7R on the proliferation of IECs.…”

Section: Discussionmentioning

confidence: 99%

Systemic blockade of P2X7 receptor protects against sepsis-induced intestinal barrier disruption

Ren

Chen

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Sepsis, during which the intestinal epithelial barrier is frequently disrupted, remains a challenging and life-threatening problem in clinical practice. The P2X7 receptor (P2X7R) is a non-selective adenosine triphosphate-gated cation channel present in macrophages that is involved in inflammatory responses. However, little is known about the role of P2X7R in macrophages during sepsis-induced intestinal barrier disruption. In this study, mice were treated with the P2X7R antagonist A740003 or the agonist BzATP by intra-peritoneal injection after the induction of gut-origin sepsis. The survival rates, inflammatory responses, intestinal barrier integrity, macrophage marker expression, and ERK and NF-κB activities were evaluated. Intestinal macrophages were also isolated and studied after exposure to Brilliant Blue G or BzATP. We found that a systemic P2X7R blockade downregulated sepsis-induced inflammatory responses and attenuated intestinal barrier dysfunction based on the evidence that mice in the A740003-treated group exhibited alleviated pro-inflammatory cytokine synthesis, intestinal hyperpermeability, epithelial apoptosis rates and tight junction damage compared with the septic mice. These changes were partly mediated by the inhibition of M1 macrophages activation via ERK/NF-κB pathways. Our data presented herein show that a P2X7R blockade could be a potential therapeutic target for the treatment of sepsis-induced intestinal barrier dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Systemic blockade of P2X7 receptor protects against sepsis-induced intestinal barrier disruption

Ren

Chen

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…However, the complete picture is probably more complicated and could be dependent upon the kind of malignancy analyzed. Purinergic receptors like P2×7R have been shown to promote cancer growth and progression in certain conditions [21, 33] while, in some case, to partially prevent cancer growth by immune infiltration [34, 35]. …”

Section: Discussionmentioning

confidence: 99%

Extracellular ATP induces apoptosis through P2X7R activation in acute myeloid leukemia cells but not in normal hematopoietic stem cells

et al. 2016

View full text Add to dashboard Cite

Recent studies have shown that high ATP levels exhibit direct cytotoxic effects on several cancer cells types. Among the receptors engaged by ATP, P2×7R is the most consistently expressed by tumors. P2×7R is an ATP-gated ion channel that could drive the opening of a non-selective pore, triggering cell-death signal. We previously demonstrated that acute myeloid leukemia (AML) cells express high level of P2×7R. Here, we show that P2×7R activation with high dose ATP induces AML blast cells apoptosis. Moreover, P2×7R is also expressed on leukemic stem/progenitor cells (LSCs) which are sensitive to ATP-mediated cytotoxicity. Conversely, this cytotoxic effect was not observed on normal hematopoietic stem/progenitor cells (HSCs). Notably, the antileukemic activity of ATP was also observed in presence of bone marrow stromal cells and its addition to the culture medium enhanced cytosine arabinoside cytotoxicity despite stroma-induced chemoresistance. Xenotransplant experiments confirmed ATP antineoplastic activity in vivo.Overall, our results demonstrate that P2×7R stimulation by ATP induced a therapeutic response in AML at the LSC level while the normal stem cell compartment was not affected. These results provide evidence that ATP would be promising for developing innovative therapy for AML.

show abstract

“…This suggests that there is a relationship between the P2X7 receptor sensitivity and the ability of these mice to respond to and eliminate intracellular pathogens because WT C57BL/6 J mice have a proline to leucine polymorphism at amino acid 451 in the C-terminal tail of the P2X7 receptor, which reduces the P2X7 sensitivity to ATP [28]. In murine model of colitis, P2X7-deficient mice showed reduced tissue damage in the colon [29] and faster recovery from epithelial damage caused by an inducing agent [30]. Nevertheless, we observed that the absence of the P2X7 receptor during in vivo infection caused by L. amazonensis resulted in more severe injury in mice.…”

Section: Discussionmentioning

confidence: 99%

The role of the P2X7 receptor in murine cutaneous leishmaniasis: aspects of inflammation and parasite control

Figliuolo

Chaves

Savio

et al. 2016

Purinergic Signalling

View full text Add to dashboard Cite

Leishmania amazonensis is the etiological agent of diffuse cutaneous leishmaniasis. The immunopathology of leishmaniasis caused by L. amazonensis infection is dependent on the pathogenic role of effector CD4 + T cells. Purinergic signalling has been implicated in resistance to infection by different intracellular parasites. In this study, we evaluated the role of the P2X7 receptor in modulating the immune response and susceptibility to infection by L. amazonensis. We found that P2X7-deficient mice are more susceptible to L. amazonensis infection than wild-type (WT) mice. P2X7 deletion resulted in increased lesion size and parasite load. Our histological analysis showed an increase in cell infiltration in infected footpads of P2X7-deficient mice. Analysis of the cytokine profile in footpad homogenates showed increased levels of IFN-γ and decreased TGF-β production in P2X7-deficient mice, suggesting an exaggerated pro-inflammatory response. In addition, we observed that CD4 + and CD8 + T cells from infected P2X7-deficient mice exhibit a higher proliferative capacity than infected WT mice. These data suggest that P2X7 receptor plays a key role in parasite control by regulating T effector cells and inflammation during L. amazonensis infection.

show abstract

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

Cited by 107 publications

References 49 publications

Systemic blockade of P2X7 receptor protects against sepsis-induced intestinal barrier disruption

Systemic blockade of P2X7 receptor protects against sepsis-induced intestinal barrier disruption

Extracellular ATP induces apoptosis through P2X7R activation in acute myeloid leukemia cells but not in normal hematopoietic stem cells

The role of the P2X7 receptor in murine cutaneous leishmaniasis: aspects of inflammation and parasite control

Contact Info

Product

Resources

About