P2X4 receptors control the fate and survival of activated microglia
Nuria Vázquez-Villoldo1, María Domercq, Abraham Martín
1Departamento de Neurociencias, Universidad del País Vasco-UPV/EHU, Barrio Sarriena s/n, 48940, Leioa, Spain, Achucarro Basque Center for Neuroscience-UPV/EHU, 48170, Zamudio, Spain, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940, Leioa, Spain.
Abstract:
Microglia, the resident immune cells of the central nervous system, responds to brain disarrangements by becoming activated to contend with brain damage. Here we show that the expression of P2X4 receptors is upregulated in inflammatory foci and in activated microglia in the spinal cord of rats with experimental autoimmune encephalomyelitis (EAE) as well as in the optic nerve of multiple sclerosis patients. To study the role of P2X4 receptors in microgliosis, we activated microglia with LPS in vitro and in vivo. We observed that P2X4 receptor activity in vitro was increased in LPS-activated microglia as assessed by patch-clamp recordings. In addition, P2X4 receptor blockade significantly reduced microglial membrane ruffling, TNFα secretion and morphological changes, as well as LPS-induced microglial cell death. Accordingly, neuroinflammation provoked by LPS injection in vivo induced a rapid microglial loss in the spinal cord that was totally prevented or potentiated by P2X4 receptor blockade or facilitation, respectively. Within the brain, microglia in the hippocampal dentate gyrus showed particular vulnerability to LPS-induced neuroinflammation. Thus, microglia processes in this region retracted as early as 2 h after injection of LPS and died around 24 h later, two features which were prevented by blocking P2X4 receptors. Together, these data suggest that P2X4 receptors contribute to controlling the fate of activated microglia and its survival.
Insights
P2X4 receptors are upregulated in activated microglia during neuroinflammation. Blocking these receptors protects microglia from death, suggesting a role in controlling microglial fate and survival in central nervous system disorders.
Area of Science:
- Neuroimmunology
- Cellular Neuroscience
Background:
- Microglia are key immune cells in the central nervous system, responding to damage by activating.
- P2X4 receptors are implicated in microglial activation and response to central nervous system injury.
Purpose of the Study:
- To investigate the role of P2X4 receptors in microgliosis and microglial survival during neuroinflammation.
Main Methods:
- Examined P2X4 receptor expression in rat EAE models and human multiple sclerosis patients.
- Activated microglia in vitro and in vivo with LPS.
- Utilized patch-clamp recordings to assess P2X4 receptor activity.
- Investigated the effects of P2X4 receptor blockade and facilitation on microglial responses and survival.
Main Results:
- P2X4 receptor expression increased in activated microglia in EAE spinal cord and MS optic nerves.
- P2X4 receptor activity was enhanced in LPS-activated microglia.
- P2X4 receptor blockade reduced microglial membrane ruffling, TNFα secretion, morphological changes, and LPS-induced cell death.
- P2X4 receptor blockade prevented LPS-induced microglial loss in vivo, while facilitation potentiated it.
- Microglia in the hippocampal dentate gyrus were particularly vulnerable, with processes retracting and cells dying post-LPS, effects prevented by P2X4 blockade.
Conclusions:
- P2X4 receptors play a critical role in regulating the survival and fate of activated microglia.
- Targeting P2X4 receptors may offer a therapeutic strategy for neuroinflammatory conditions.
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