Role of extracellular nucleotides in the immune response against intracellular bacteria and protozoan parasites

Coutinho‐Silva, Robson; Ojcius, David M.

doi:10.1016/j.micinf.2012.05.009

Cited by 84 publications

(81 citation statements)

References 79 publications

(85 reference statements)

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“…Bars represent the mean ± standard error of the mean of three independent experiments performed with three animals. *p < 0.05; **p < 0.01 using Student's t test and one-way ANOVA coupled to Tukey's post hoc test comparing infected P2X7 KO and WT mice at the same timepoint [13,24,25]. The role of the P2X7 receptor in a wide range of infectious diseases has been studied in vitro and in vivo using P2X7 KO mice [10,26,27].…”

Section: Discussionmentioning

confidence: 99%

“…P2X7 receptor stimulation leads to the activation of multiple immune signalling pathways, including the MyD88/NFκB pathway and the phospholipase D pathway [12]. In addition, this receptor induces ROS production and apoptosis, mechanisms that have important anti-pathogenic roles [13]. ATP also rapidly induces autophagy in human and mouse macrophages, resulting in mycobacterial killing in a process dependent on Ca ++ influx [14].…”

Section: Introductionmentioning

confidence: 99%

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

Figliuolo

Chaves

Savio

et al. 2016

Purinergic Signalling

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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

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“…The role of ATPe during protozoan infection has also been studied. It has been demonstrated that the P2X7 receptor participates in the elimination of many intracellular parasites (26). The role of the P2X7 receptor via ATPe has been demonstrated in Toxoplasma gondii infection.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene B4 Modulates P2X7 Receptor–MediatedLeishmania amazonensisElimination in Murine Macrophages

Chaves

Marques-da-Silva

Monteiro

et al. 2014

The Journal of Immunology

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ATP is an important signaling molecule in the immune system, and it is able to bind the P2X7 purinergic receptor. Recently, our group showed that ATP-treated macrophages eliminate Leishmania amazonensis. It has been reported that leukotriene B4 (LTB4) reduces the parasitic load of infected macrophages. Additionally, it has been demonstrated that the P2X7 receptor can induce PLA2 activation and arachidonic acid mobilization. Based on these findings, we investigated whether LTB4 is produced upon P2X7 receptor activation and examined whether LTB4 modulates parasite elimination. Using macrophages lacking the P2X7 receptor, we observed that ATP was not able to reduce L. amazonensis load. This result suggests a role of the P2X7 purinergic receptor in parasite elimination. In addition, ATP was sufficient to induce LTB4 release from infected control macrophages but not from macrophages lacking the P2X7 receptor. Moreover, we found that ATP failed to decrease the parasitic load in 5-lipoxygenase (LO)–deficient macrophages. Treatment with the 5-LO inhibitor AA861 also impairs the ATP effect on parasitic loads. Furthermore, macrophages from 5-LO knockout mice eliminated L. amazonensis in the presence of exogenous LTB4, and macrophages obtained from P2X7 receptor knockout mice eliminated L. amazonensis when incubated with ionomycin. Finally, we demonstrated that in the presence of CP105696, an antagonist for LTB4 high-affinity receptor, ATP was not able to reduce parasitic load. These results indicate that P2X7 receptor activation leads to LTB4 formation, which is required for L. amazonensis elimination.

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“…Compelling evidence implicates P2XR during inflammation and immune response against microbes 72,78 . Although several other P2XRs are functional during inflammation (for example, P2X 4 R), P2X 7 R in particular has been shown to affect the outcomes of inflammatory or infectious diseases.…”

Section: P2xr Signalling During Inflammationmentioning

confidence: 99%

Nucleotide signalling during inflammation

Idzko

Ferrari

Eltzschig

2014

Nature

753

709

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Inflammatory conditions are associated with the extracellular release of nucleotides, particularly ATP. In the extracellular compartment, ATP predominantly functions as a signalling molecule through the activation of purinergic P2 receptors. Metabotropic P2Y receptors are G-protein-coupled, whereas ionotropic P2X receptors are ATP-gated ion channels. Here we discuss how signalling events through P2 receptors alter the outcomes of inflammatory or infectious diseases. Recent studies implicate a role for P2X/P2Ysignalling in mounting appropriate inflammatory responses critical for host defence against invading pathogens or tumours. Conversely, P2X/P2Y signalling can promote chronic inflammation during ischaemia and reperfusion injury, inflammatory bowel disease or acute and chronic diseases of the lungs. Although nucleotide signalling has been used clinically in patients before, research indicates an expanding field of opportunities for specifically targeting individual P2 receptors for the treatment of inflammatory or infectious diseases.

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Role of extracellular nucleotides in the immune response against intracellular bacteria and protozoan parasites

Cited by 84 publications

References 79 publications

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

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

Leukotriene B4 Modulates P2X7 Receptor–MediatedLeishmania amazonensisElimination in Murine Macrophages

Nucleotide signalling during inflammation

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