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Updated: Mar 14, 2026
Two-photon Imaging of Microglial Processes' Attraction Toward ATP or Serotonin in Acute Brain Slices
Published on: January 31, 2019
ATP-induced IL-1β secretion is selectively impaired in microglia as compared to hematopoietic macrophages
Saskia Maria Burm1, Ella Alwine Zuiderwijk-Sick1, Paola Massiel Weert1
1Alternatives Unit, Biomedical Primate Research Centre, Lange Kleiweg 161, 2288 GJ Rijswijk, The Netherlands.
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.
Insights
Extracellular ATP triggers inflammasome activation and IL-1β secretion. Microglia, unlike macrophages, show reduced IL-1β release due to distinct purinergic receptor usage, potentially protecting the central nervous system.
Area of Science:
- Neuroimmunology
- Innate Immunity
- Cellular Signaling
Background:
- Extracellular nucleotides, like ATP, signal danger via purinergic receptors (P2X, P2Y).
- High extracellular ATP concentrations activate P2X7 receptors, leading to inflammasome activation and pro-inflammatory cytokine release (e.g., IL-1β).
- Microglia are key innate immune cells in the central nervous system (CNS) and their inflammasome responses are critical in neurodegeneration.
Purpose of the Study:
- To compare ATP-induced IL-1β secretion between primary rhesus macaque microglia and bone marrow-derived macrophages (BMDM).
- To investigate the role of purinergic receptors in mediating IL-1β secretion in these cell types.
- To understand cell type-specific differences in innate immune responses within the CNS.
Main Methods:
- Primary rhesus macaque microglia and BMDM were cultured.
- ATP-induced IL-1β secretion was measured.
- Full expression profiles of P2 receptors were assessed.
- Purinergic receptor agonists and antagonists were used to determine signaling pathways.
Main Results:
- Microglia secreted significantly lower levels of IL-1β in response to ATP compared to BMDM.
- Differences in IL-1β secretion were attributed to variations in purinergic receptor expression and usage, not ATP metabolism.
- BMDM IL-1β secretion was P2X7-dependent, while microglia involved multiple receptors, including P2X7 and P2X4.
Conclusions:
- Microglia exhibit distinct purinergic receptor-mediated regulation of IL-1β secretion compared to BMDM.
- These cell-specific immune responses may represent adaptations to the unique and vulnerable CNS environment.
- Understanding these differences is crucial for developing targeted therapies for neurodegenerative diseases.
