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

Author:

Savio Luiz Eduardo Baggio1ORCID,de Andrade Mello Paola2,Santos Stephanie Alexia Cristina Silva3ORCID,de Sousa Júlia Costa3,Oliveira Suellen D. S.4ORCID,Minshall Richard D.45ORCID,Kurtenbach Eleonora3,Wu Yan2,Longhi Maria Serena2ORCID,Robson Simon C.2,Coutinho-Silva Robson1ORCID

Affiliation:

1. Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

2. Departments of Medicine and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA

3. Laboratory of Molecular Biology and Biochemistry of Proteins, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

4. Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA

5. Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA

Abstract

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.

Funder

National Institutes of Health

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro

Publisher

The Company of Biologists

Subject

Cell Biology

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