Microglial migration mediated by ATP-induced ATP release from lysosomes.
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 Ca(2+)-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.
Institute of Neuroscience and Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Ying
Y
Dou
Hang-jun
HJ
Wu
Hui-quan
HQ
Li
Song
S
Qin
Yin-er
YE
Wang
Jing
J
Li
Hui-fang
HF
Lou
Zhong
Z
Chen
Xiao-ming
XM
Li
Qing-ming
QM
Luo
Shumin
S
Duan
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002633:Chemotaxis; D005089:Exocytosis; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058470:Receptors, Purinergic P2Y / Q000378:metabolism; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000378:metabolism
D058470:Receptors, Purinergic P2Y; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate; D020691:rab GTP-Binding Proteins; D002118:Calcium