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NTPDase1 activity attenuates microglial phagocytosis

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Abstract

Purinergic signaling plays a major role in the regulation of phagocytosis in microglia. Interplay between P2 and P1 receptor activation is controlled by a cascade of extracellular enzymes which dephosphorylate purines resulting in the formation of adenosine. The ATP- and ADP-degrading capacity of cultured microglia depends on the expression of ecto-nucleoside triphosphate diphosphohydrolase 1 (CD39) and is several times higher when compared to astrocytes which lack this enzyme. In brain slices, deletion of CD39 resulted in a 50 % decrease of ADP-degrading ability, while the degradation of ATP was decreased to about 75 % of the values measured in wild-type brain tissue. Microglia in acute slices from cd39−/− animals had increased constitutive phagocytic activity which could not be further enhanced by ATP in contrast to control animals. Pharmacological blockage of P2 receptors decreased the constitutive phagocytic activity to a similar base level in wild-type and cd39−/− microglia. Activation of P1 receptors by non-hydrolysable adenosine analog significantly decreased phagocytic activity. Deletion of CD73, an enzyme expressed by microglia which converts AMP to adenosine did not affect phagocytic activity. Taken together, these data show that CD39 plays a prominent role in controlling ATP levels and thereby microglial phagocytosis.

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Abbreviations

E-NTPDase:

Ecto-nucleoside triphosphate diphosphohydrolase

ACSF:

Artificial cerebrospinal fluid

PPADS:

Pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium salt

NECA:

1-(6-Amino-9H-purin-9-yl)-1-deoxy-N-ethyl-β-D-ribofuranuronamide

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Acknowledgments

This work was supported by Deutsche Forschungsgemeinschaft. We thank Regina Piske, Irene Haupt, and the staff of microscopy core facility at the Max Delbrueck Center for Molecular Medicine for technical assistance.

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Author notes

  1. Grietje Krabbe

    Present address: Gladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA

Authors and Affiliations

  1. Department for Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine, Berlin, 13125, Germany

    Larisa Bulavina, Frank Szulzewsky, Adriana Rocha, Grietje Krabbe, Vitali Matyash & Helmut Kettenmann

  2. Division of Gastroenterology, Harvard Medical School, Boston, MA, 02215, USA

    Simon C. Robson

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  1. Larisa Bulavina
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  2. Frank Szulzewsky
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Correspondence to Helmut Kettenmann.

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Vitali Matyash and Helmut Kettenmann contributed equally to this paper.

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Bulavina, L., Szulzewsky, F., Rocha, A. et al. NTPDase1 activity attenuates microglial phagocytosis. Purinergic Signalling 9, 199–205 (2013). https://doi.org/10.1007/s11302-012-9339-y

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  • DOI: https://doi.org/10.1007/s11302-012-9339-y

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