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Microglial activation by purines and pyrimidines
1Section of Neuropharmacology, Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
Abstract:
Microglial activation by purines and pyrimidines is reviewed, with emphasis on the actions of adenosine 5'-triphosphate (ATP) on chemotaxis or releases of plasminogen and cytokines from microglia. ATP activates microglia, causing morphological changes with membrane ruffling. Activated microglia exhibit chemotaxis to ATP. Microglia stimulated by a low concentration of ATP (approximately 30-50 microM) rapidly release plasminogen (within 5-10 min), which may protect neurons. Microglia stimulated by a higher concentration of ATP release tumor necrosis factor-alpha (TNF-alpha), 2-3 h after the stimulation and interleukin-6 (IL-6), 6 h after the stimulation. It is reported that TNF-alpha stimulation causes an increase in the expression of IL-6 receptor mRNA and expression in neuronal cells (März et al. 1996. Brain Res 706:71-79). After binding with gp130, the IL-6 receptor matures and can accept IL-6 molecules. It is speculated that neurons may require several hours to prepare for the full reception of IL-6, which induces a more efficient protective effect by IL-6 after stimulation with TNF-alpha. After neurons are ready to accept IL-6 fully, microglia release IL-6 to neurons. Stronger and longer stimulation by ATP may change the function of microglia and cause cell death. The conditions evoking the heavy stimulation would result from serious injury. Activated microglia act as scavenger cells that induce apoptosis in damaged neurons by releasing toxic factors, including NO, and removing dead cells, their remnants, or dangerous debris by phagocytosis. These actions lead to a suitable environment for tissue repair and neural regeneration. The fate of neurons may therefore be regulated in part by ATP through the activation of microglia.
Insights
Adenosine triphosphate (ATP) activates microglia, influencing neuronal protection and repair. Microglia release factors that protect neurons at low ATP levels and promote cell death at high levels, regulating neural fate.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the immune cells of the central nervous system, play crucial roles in neuroinflammation and tissue repair.
- Purinergic signaling, particularly involving adenosine triphosphate (ATP), is increasingly recognized for its modulatory effects on microglial function.
Purpose of the Study:
- To review the activation of microglia by purines and pyrimidines, focusing on ATP's effects.
- To elucidate the mechanisms by which ATP influences microglial chemotaxis, cytokine release, and neuronal interactions.
Main Methods:
- Review of existing literature on microglial activation by purinergic signaling.
- Analysis of ATP concentration-dependent effects on microglial responses, including morphological changes, chemotaxis, and the release of plasminogen and cytokines (TNF-alpha, IL-6).
Main Results:
- ATP activates microglia, inducing morphological changes and chemotaxis.
- Low ATP concentrations stimulate rapid plasminogen release, potentially protecting neurons.
- Higher ATP concentrations lead to the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), with delayed neuronal receptivity to IL-6.
- Excessive ATP stimulation can result in microglial cell death and the release of toxic factors, contributing to apoptosis of damaged neurons.
Conclusions:
- ATP signaling is a critical regulator of microglial function, influencing both neuroprotection and neurodegeneration.
- Microglia, activated by ATP, orchestrate processes of tissue repair and neural regeneration through scavenger functions and the release of signaling molecules.
- The concentration and duration of ATP stimulation dictate the ultimate fate of neurons, highlighting a complex interplay between purinergic signaling and neural health.