ATP induced microglial cell migration through non-transcriptional activation of matrix metalloproteinase-9.
In response to brain insults, microglia, the resident inflammatory cells in CNS, migrate into injured sites to initiate inflammatory responses in brain. ATP, released from apoptotic or necrotic cells induce chemoattractive responses but the mechanism is not clear yet. In this study, we investigated whether ATP modulates microglial migration by regulating the activity of matrix metalloproteinases (MMPs). ATP induced rapid microglial migration and increased the activity of MMP-9 in the culture supernatants (secreted compartments) in a concentration-dependent manner. The increased activity of secreted MMP-9 is due to the increased protein secretion, but not by the increased MMP-9 mRNA and protein expression. Inhibition of MMP-9 activity by treatment with specific inhibitors including GM6001 and SB-3CT prevented ATP-induced microglial migration. ATP-induced microglial migration was also inhibited by P2Y receptor antagonists including clopidogrel as well as PI3K inhibitor such as wortmanin. Taken together, ATP non-transcriptionally increased MMP-9 activity by activation of P2Y and PI3K. The results from the present investigation may provide further insights into the regulation of the activity of MMP-9 during microglial migration, which may play essential role in the regulation of inflammatory responses in pathological situations such as neurodegenerative disorders.
Choi
Min Sik
MS
Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
Cho
Kyu Suk
KS
Shin
Sun Mi
SM
Ko
Hyun Myung
HM
Kwon
Kyung Ja
KJ
Shin
Chan Young
CY
Ko
Kwang Ho
KH
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D000077144:Clopidogrel; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D013450:Sulfones / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D004151:Dipeptides; D006573:Heterocyclic Compounds, 1-Ring; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058919:Purinergic P2 Receptor Antagonists; C429533:SB 3CT compound; D013450:Sulfones; D000255:Adenosine Triphosphate; D000077144:Clopidogrel; D020780:Matrix Metalloproteinase 9; D013988:Ticlopidine; D000077191:Wortmannin