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ATP induced microglial cell migration through non-transcriptional activation of matrix metalloproteinase-9

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Abstract

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.

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Authors and Affiliations

  1. Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Korea

    Min Sik Choi, Kyu Suk Cho, Sun Mi Shin & Kwang Ho Ko

  2. Institute for Biomedical Sciences and Technology, and Institute of Functional Genomics, Konkuk University, Seoul, 143-701, Korea

    Hyun Myung Ko, Kyung Ja Kwon & Chan Young Shin

  3. Department of Pharmacology, School of Medicine, Konkuk University, Seoul, 143-701, Korea

    Hyun Myung Ko & Chan Young Shin

  4. Research Institute of Medical Sciences, School of Medicine, Konkuk University, Seoul, 143-701, Korea

    Chan Young Shin

  5. Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea

    Kwang Ho Ko

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  1. Min Sik Choi
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  2. Kyu Suk Cho
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  3. Sun Mi Shin
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Correspondence to Chan Young Shin or Kwang Ho Ko.

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Choi, M.S., Cho, K.S., Shin, S.M. et al. ATP induced microglial cell migration through non-transcriptional activation of matrix metalloproteinase-9. Arch. Pharm. Res. 33, 257–265 (2010). https://doi.org/10.1007/s12272-010-0211-8

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  • DOI: https://doi.org/10.1007/s12272-010-0211-8

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