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Author Notes:

Correspondence should be addressed to A.G.O. (anna.orr@gladstone.ucsf.edu) or S.F.T. (strayne@emory.edu)

AUTHOR CONTRIBUTIONS A.G.O. designed and carried out the study, collected and analyzed data, and wrote the paper; A.L.O. helped carry out in vivo experiments, brain tissue processing, and manuscript revisions; X.J.L. provided surgical equipment and immunohistochemical reagents, R.E.G. provided human tissue samples and helped with experimental design and interpretation; S.F.T was involved in study design, interpretation of data, and revision of the manuscript and figures.

Subject:

Research Funding:

National Institute of Environmental Health Sciences : NIEHS

National Institute of Neurological Disorders and Stroke : NINDS

Adenosine A2A receptor mediates microglial process retraction

Tools:

Journal Title:

Nature Neuroscience

Volume:

Volume 12, Number 7

Publisher:

, Pages 872-878

Type of Work:

Article | Post-print: After Peer Review

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 motile processes. Motility of these processes is guided by local release of chemoattractants. However, most microglial processes retract during prolonged brain injury or disease. This hallmark of brain inflammation remains unexplained. Here we identified a molecular pathway in mouse and human microglia that converts ATP-driven process extension into process retraction during inflammation. This chemotactic reversal was driven by upregulation of the A2A adenosine receptor coincident with P2Y12 downregulation. Thus, A2A 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.
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