Adenosine A(2A) receptor mediates microglial process retraction.
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.
Orr
Anna G
AG
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA. anna.orr@gladstone.ucsf.edu
Orr
Adam L
AL
Li
Xiao-Jiang
XJ
Gross
Robert E
RE
Traynelis
Stephen F
SF
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D018920:Coculture Techniques; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction / Q000502:physiology; D014741:Video Recording
D058908:Adenosine A2 Receptor Agonists; D008070:Lipopolysaccharides; D018377:Neurotransmitter Agents; C548576:P2RY12 protein, human; C548577:P2ry12 protein, mouse; D010627:Phenethylamines; D012333:RNA, Messenger; D043683:Receptors, Adenosine A2; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000255:Adenosine Triphosphate; D000241:Adenosine