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POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

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Abstract

Extracellular nucleotides can modulate the immunological response by activating purinergic receptors (P2Rs) on the cell surface of macrophages, dendritic, and other immune cells. In particular, the activation of P2X7R can induce release of cytokines and cell death as well as the uptake of large molecules through the cell membrane by a mechanism still poorly understood. Polyoxotungstate-1 (POM-1) has been proposed as a potent inhibitor of ecto-nucleotidases, enzymes that hydrolyze extracellular nucleotides, regulating the activity of P2Rs. However, the potential impact of POM-1 on P2Rs has not been evaluated. Here, we used fluorescent dye uptake, cytoplasmic free Ca2+ concentration measurement, patch-clamp recordings, scanning electron microscopy, and quantification of inflammatory mediators to investigate the effects of POM-1 on P2Rs of murine macrophages. We observed that POM-1 blocks the P2YR-dependent cytoplasmic Ca2+ increase and has partial effects on the cytoplasmic Ca2+, increasing dependence on P2XRs. POM-1 can inhibit the events related with ATP-dependent inflammasome activation, anionic dye uptake, and also the opening of large conductance channels, which are associated with P2X7R-dependent pannexin-1 activation. On the other hand, this compound has no effects on cationic fluorescent dye uptake, apoptosis, and bleb formation, also dependent on P2X7R. Moreover, POM-1 can be considered an anti-inflammatory compound, because it prevents TNF-α and nitric oxide release from LPS-treated macrophages.

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Acknowledgements

We thank the National Institute of Science and Technology for Structural Biology and Bioimaging—Microscopy Division (CENABIO-UFRJ) for allowing use of the scanning electron microscope.

Funding

This research received financial support from CNPq, FAPERJ and FINEP.

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Authors and Affiliations

  1. Instituto de Biofísica Carlos Chagas Filho da Universidade Federal de Rio de Janeiro, Rio de Janeiro, Brazil

    Gabriela Pimenta-dos-Reis, Paula Gabriela Quintana, Lincon Onorio Vidal, Bárbara Andréa Fortes dos Santos, Norton Heise & Pedro Muanis Persechini

  2. Laboratório de Helmintologia Romero Lascasas Porto, Departamento de Microbiologia, Imunologia e Parasitologia. Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

    Eduardo José Lopes Torres

  3. Microbiota Research Center, Chang Gung University, Taoyuan, Taiwan

    Chuan-Sheng Lin & Julieta Schachter

  4. Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan

    Chuan-Sheng Lin

  5. Polo Xerem, Universidade Federal de Rio de Janeiro, Estrada de Xerém No. 27, Xerém, Duque de Caxias, Rio de Janeiro, 25245-390, Brazil

    Julieta Schachter

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  1. Gabriela Pimenta-dos-Reis
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  8. Pedro Muanis Persechini
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  9. Julieta Schachter
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Correspondence to Julieta Schachter.

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Conflicts of interest

Gabriela Pimenta-dos-Reis declares that she has no conflict of interest.

Eduardo José Lopes Torres declares that he has no conflict of interest.

Paula Gabriela Quintana declares that she has no conflict of interest.

Lincon Onorio Vidal declares that he has no conflict of interest.

Bárbara Andréa Fortes dos Santos declares that she has no conflict of interest.

Chuan-Sheng Lin declares that he has no conflict of interest.

Norton Heise declares that he has no conflict of interest.

Pedro Muanis Persechini declares that he has no conflict of interest.

Julieta Schachter declares that she has no conflict of interest.

Ethical approval

All animals were used according to the guidelines for animal use in scientific experiments of the Carlos Chagas Filho Institute of Biophysics of Federal University of Rio de Janeiro. The protocols were approved by the Research Ethics Committee on Animal Care of the Health Science Center of Federal University of Rio de Janeiro (protocol number 001200.001568/2013-87).

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Pimenta-dos-Reis, G., Torres, E.J.L., Quintana, P.G. et al. POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages. Purinergic Signalling 13, 611–627 (2017). https://doi.org/10.1007/s11302-017-9588-x

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  • DOI: https://doi.org/10.1007/s11302-017-9588-x

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