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Adenosine A(2A) receptor mediates microglial process retraction.

TitleAdenosine A(2A) receptor mediates microglial process retraction.
Publication TypeJournal Article
Year of Publication2009
AuthorsOrr AG, Orr AL, Li X-J, Gross RE, Traynelis SF
JournalNat Neurosci
Volume12
Issue7
Pagination872-8
Date Published2009 Jul
ISSN1546-1726
KeywordsAdenosine, Adenosine A2 Receptor Agonists, Adenosine Triphosphate, Animals, Astrocytes, Cells, Cultured, Chemotaxis, Coculture Techniques, Humans, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Neurotransmitter Agents, Phenethylamines, Receptors, Adenosine A2, Receptors, Purinergic P2, Receptors, Purinergic P2Y12, RNA, Messenger, Signal Transduction, Video Recording
Abstract

Cell motility drives many biological processes, including immune responses and embryonic development. In the brain, microglia are immune cells that survey and scavenge brain tissue using elaborate and motile cell processes. The motility of these processes is guided by the local release of chemoattractants. However, most microglial processes retract during prolonged brain injury or disease. This hallmark of brain inflammation remains unexplained. We identified a molecular pathway in mouse and human microglia that converted ATP-driven process extension into process retraction during inflammation. This chemotactic reversal was driven by upregulation of the A(2A) adenosine receptor coincident with P2Y(12) downregulation. Thus, A(2A) receptor stimulation by adenosine, a breakdown product of extracellular ATP, caused activated microglia to assume their characteristic amoeboid morphology during brain inflammation. Our results indicate that purine nucleotides provide an opportunity for context-dependent shifts in receptor signaling. Thus, we reveal an unexpected chemotactic switch that generates a hallmark feature of CNS inflammation.

DOI10.1038/nn.2341
Alternate JournalNat. Neurosci.
PubMed ID19525944
PubMed Central IDPMC2712729
Grant ListT32 ES012870 / ES / NIEHS NIH HHS / United States
P01 ES016731 / ES / NIEHS NIH HHS / United States
F31 NS054515-01A1 / NS / NINDS NIH HHS / United States
F31 NS054515 / NS / NINDS NIH HHS / United States
P01 ES016731-01 / ES / NIEHS NIH HHS / United States