title: ATP-induced IL-1β secretion is selectively impaired in microglia as compared to hematopoietic macrophages.
abstract: Under stressful conditions nucleotides are released from dying cells into the extracellular space, where they can bind to purinergic P2X and P2Y receptors. High concentrations of extracellular ATP in particular induce P2X7-mediated signaling, which leads to inflammasome activation. This in turn leads to the processing and secretion of pro-inflammatory cytokines, like interleukin (IL)-1β. During neurodegenerative diseases, innate immune responses are shaped by microglia and we have previously identified microglia-specific features of inflammasome-mediated responses. Here, we compared ATP-induced IL-1β secretion in primary rhesus macaque microglia and bone marrow-derived macrophages (BMDM). We assessed the full expression profile of P2 receptors and characterized the induction and modulation of IL-1β secretion by extracellular nucleotides. Microglia secreted significantly lower levels of IL-1β in response to ATP when compared to BMDM. We demonstrate that this is not due to differences in sensitivity, kinetics or expression of ATP-processing enzymes, but rather to differences in purinergic receptor expression levels and usage. Using a combined approach of purinergic receptor agonists and antagonists, we demonstrate that ATP-induced IL-1β secretion in BMDM was fully dependent on P2X7 signaling, whereas in microglia multiple purinergic receptors were involved, including P2X7 and P2X4. These cell type-specific features of conserved innate immune responses may reflect adaptations to the vulnerable CNS microenvironment. GLIA 2016;64:2231-2246.
authors.affiliation: Alternatives Unit, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ Rijswijk, The Netherlands.
authors.forename: Saskia Maria
authors.initials: SM
authors.lastname: Burm
authors.affiliation: Alternatives Unit, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ Rijswijk, The Netherlands.
authors.forename: Ella Alwine
authors.initials: EA
authors.lastname: Zuiderwijk-Sick
authors.affiliation: Alternatives Unit, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ Rijswijk, The Netherlands.
authors.forename: Paola Massiel
authors.initials: PM
authors.lastname: Weert
authors.affiliation: Alternatives Unit, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ Rijswijk, The Netherlands. bajramovic@bprc.nl.
authors.forename: Jeffrey John
authors.initials: JJ
authors.lastname: Bajramovic
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008253:Macaca mulatta; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D011134:Polysaccharides / Q000494:pharmacology; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D058469:Receptors, Purinergic P2X / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D011134:Polysaccharides; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D012333:RNA, Messenger; D058469:Receptors, Purinergic P2X; D000255:Adenosine Triphosphate
keywords: P2X4; P2X7; macrophages; purinergic receptor; tissue-specific