Microglial migration mediated by ATP-induced ATP release from lysosomes
- 10 January 2012
- journal article
- Published by Springer Science and Business Media LLC in Cell Research
- Vol. 22 (6), 1022-1033
- https://doi.org/10.1038/cr.2012.10
Abstract
Microglia are highly motile cells that act as the main form of active immune defense in the central nervous system. Attracted by factors released from damaged cells, microglia are recruited towards the damaged or infected site, where they are involved in degenerative and regenerative responses and phagocytotic clearance of cell debris. ATP release from damaged neural tissues has been suggested to mediate the rapid extension of microglial process towards the site of injury. However, the mechanisms of the long-range migration of microglia remain to be clarified. Here, we found that lysosomes in microglia contain abundant ATP and exhibit Ca2+-dependent exocytosis in response to various stimuli. By establishing an efficient in vitro chemotaxis assay, we demonstrated that endogenously-released ATP from microglia triggered by local microinjection of ATPγS is critical for the long-range chemotaxis of microglia, a response that was significantly inhibited in microglia treated with an agent inducing lysosome osmodialysis or in cells derived from mice deficient in Rab 27a (ashen mice), a small GTPase required for the trafficking and exocytosis of secretory lysosomes. These results suggest that microglia respond to extracellular ATP by releasing ATP themselves through lysosomal exocytosis, thereby providing a positive feedback mechanism to generate a long-range extracellular signal for attracting distant microglia to migrate towards and accumulate at the site of injury.Keywords
This publication has 40 references indexed in Scilit:
- Mechanisms of interleukin-1β releaseImmunobiology, 2009
- Resolving vesicle fusion from lysis to monitor calcium-triggered lysosomal exocytosis in astrocytesProceedings of the National Academy of Sciences of the United States of America, 2007
- Rab27b Regulates Mast Cell Granule Dynamics and SecretionTraffic, 2007
- UDP acting at P2Y6 receptors is a mediator of microglial phagocytosisNature, 2007
- Rab27b regulates number and secretion of platelet dense granulesProceedings of the National Academy of Sciences of the United States of America, 2007
- P2X7 receptors: Properties and relevance to CNS functionGlia, 2006
- Like cops on the beat: the active role of resting microgliaTrends in Neurosciences, 2005
- Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in VivoScience, 2005
- Plasma Membrane Repair Is Mediated by Ca2+-Regulated Exocytosis of LysosomesCell, 2001
- Secretory lysosomes — a special mechanism of regulated secretion in haemopoietic cellsTrends in Cell Biology, 1996