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The ectonucleotidase cd39/ENTPDase1 modulates purinergic-mediated microglial migration
Katrin Färber1, Sören Markworth, Ulrike Pannasch
1Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Abstract:
Microglia is activated by brain injury. They migrate in response to ATP and although adenosine alone has no effect on wild type microglial migration, we show that inhibition of adenosine receptors impedes ATP triggered migration. CD39 is the dominant cellular ectonucleotidase that degrades nucleotides to nucleosides, including adenosine. Importantly, ATP fails to stimulate P2 receptor mediated migration in cd39(-/-) microglia. However, the effects of ATP on migration in cd39(-/-) microglia can be restored by co-stimulation with adenosine or by addition of a soluble ectonucleotidase. We also tested the impact of cd39-deletion in a model of ischemia, in an entorhinal cortex lesion and in the facial nucleus after facial nerve lesion. The accumulation of microglia at the pathological sites was markedly decreased in cd39(-/-) animals. We conclude that the co-stimulation of purinergic and adenosine receptors is a requirement for microglial migration and that the expression of cd39 controls the ATP/adenosine balance.
Insights
Microglia migration requires both purinergic and adenosine receptor co-stimulation. The enzyme CD39 is crucial for this process by balancing adenosine levels, impacting brain injury responses.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's immune cells, are activated by injury.
- Microglial migration is essential for clearing debris and initiating repair.
- ATP and adenosine are key signaling molecules in the brain.
Purpose of the Study:
- To investigate the role of CD39 in microglial migration.
- To determine the necessity of adenosine co-stimulation for ATP-induced microglial migration.
- To elucidate the ATP/adenosine balance controlled by CD39 in microglial responses.
Main Methods:
- Utilized wild-type and CD39-deficient (cd39(-/-)) microglia.
- Assessed microglial migration in response to ATP and adenosine.
- Examined microglial accumulation in models of brain injury (ischemia, entorhinal cortex lesion, facial nerve lesion).
Main Results:
- ATP-triggered microglial migration was impaired in cd39(-/-) microglia.
- Adenosine co-stimulation or addition of soluble ectonucleotidase restored ATP-induced migration in cd39(-/-) microglia.
- Microglial accumulation at pathological sites was significantly reduced in cd39(-/-) animals.
Conclusions:
- Co-stimulation of purinergic and adenosine receptors is essential for microglial migration.
- CD39 plays a critical role in regulating the ATP/adenosine balance, thereby controlling microglial migration.
- Targeting CD39 could modulate microglial responses in neurological disorders.
