P2X7 receptor activation increases caveolin-1 expression and macrophage lipid raft formation boosting CD39 activity

Macrophages are tissue-resident immune cells crucial for the initiation and maintenance of immune responses. Purinergic signaling modulates macrophage activity and impacts cellular plasticity. The ATP-activated purinergic receptor P2X7 has pro-inflammatory properties, which contribute to macrophage...

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Bibliographic Details
Published inJournal of cell science
Main Authors Savio, Luiz Eduardo Baggio, de Andrade Mello, Paola, Santos, Stephanie Alexia Cristina Silva, de Sousa, Júlia Costa, Oliveira, Suellen D S, Minshall, Richard D, Kurtenbach, Eleonora, Wu, Yan, Longhi, Maria Serena, Robson, Simon C, Coutinho-Silva, Robson
Format Journal Article
LanguageEnglish
Published England 01.01.2020
Subjects
Lipid rafts
Extracellular ATP
Macrophages
Ectonucleotidases
Purinergic signaling
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Summary:Macrophages are tissue-resident immune cells crucial for the initiation and maintenance of immune responses. Purinergic signaling modulates macrophage activity and impacts cellular plasticity. The ATP-activated purinergic receptor P2X7 has pro-inflammatory properties, which contribute to macrophage activation. P2X7 receptor signaling is in turn modulated by ectonucleotidases such as CD39/E-NTPDase1, expressed in caveolae and lipid rafts. Here, we examined P2X7 receptor activity and determined impacts on ectonucleotidase localization and function in LPS-primed macrophages. First, we verified that ATP boosted CD39 activity and caveolin-1 expression in LPS-primed macrophages. Drugs that disrupt cholesterol-enriched domains - such as nystatin and methyl-β-cyclodextrin - decreased CD39 enzymatic activity in all circumstances. We noted that CD39 colocalized with lipid raft markers (flotillin-2 and caveolin-1) in LPS-primed macrophages treated with ATP. P2X7 receptor inhibition blocked these ATP-mediated increases in caveolin-1 expression and inhibited the colocalization with CD39. Further, we found that STAT3 activation is significantly attenuated in LPS and LPS+BzATP-treated caveolin-1 deficient macrophages. Taken together, our data suggest that P2X7 receptor triggers the initiation of lipid raft-dependent mechanisms that upregulates CD39 activity and could contribute to limit macrophage responses restoring homeostasis.
ISSN:1477-9137