ATP and NO dually control migration of microglia to nerve lesions

Microglia migrate rapidly to lesions in the central nervous system (CNS), presumably in response to chemoattractants including ATP released directly or indirectly by the injury. Previous work on the leech has shown that nitric oxide (NO), generated at the lesion, is both a stop signal for microglia...

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Published in:Developmental neurobiology (Hoboken, N.J.) N.J.), 2009-01, Vol.69 (1), p.60-72
Main Authors: Duan, Yuanli, Sahley, Christie L., Muller, Kenneth J.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - pharmacology
Aminoquinolines - pharmacology
Analysis of Variance
Animals
cell movement
Cell Movement - drug effects
CNS injury
Cyclic GMP - metabolism
Cyclic N-Oxides - pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Free Radical Scavengers - pharmacology
Hirudinea
Imidazoles - pharmacology
In Vitro Techniques
Leeches
Microglia - drug effects
Microglia - physiology
nerve injury
nerve regeneration
Nitric Oxide - metabolism
Nucleotides - pharmacology
purinergic receptors
Trauma, Nervous System - pathology
Trauma, Nervous System - physiopathology
Triazines
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Summary:Microglia migrate rapidly to lesions in the central nervous system (CNS), presumably in response to chemoattractants including ATP released directly or indirectly by the injury. Previous work on the leech has shown that nitric oxide (NO), generated at the lesion, is both a stop signal for microglia at the lesion and crucial for their directed migration from hundreds of micrometers away within the nerve cord, perhaps mediated by a soluble guanylate cyclase (sGC). In this study, application of 100 μM ATP caused maximal movement of microglia in leech nerve cords. The nucleotides ADP, UTP, and the nonhydrolyzable ATP analog AMP‐PNP (adenyl‐5′‐yl imidodiphosphate) also caused movement, whereas AMP, cAMP, and adenosine were without effect. Both movement in ATP and migration after injury were slowed by 50 μM reactive blue 2 (RB2), an antagonist of purinergic receptors, without influencing the direction of movement. This contrasted with the effect of the NO scavenger cPTIO (2‐(4‐carboxyphenyl)‐4,4,5,5‐teramethylimidazoline‐oxyl‐3‐oxide), which misdirected movement when applied at 1 mM. The cPTIO reduced cGMP immunoreactivity without changing the immunoreactivity of eNOS (endothelial nitric oxide synthase), which accompanies increased NOS activity after nerve cord injury, consistent with involvement of sGC. Moreover, the sGC‐specific inhibitor LY83583 applied at 50 μM had a similar effect, in agreement with previous results with methylene blue. Taken together, the experiments support the hypothesis that ATP released directly or indirectly by injury activates microglia to move, whereas NO that activates sGC directs migration of microglia to CNS lesions. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2009
ISSN:1932-8451
1932-846X
DOI:10.1002/dneu.20689