Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death

W. Lee Titsworth, Xiaoxin Cheng, Yan Ke, Lingxiao Deng, Kenneth A. Burckardt, Chris Pendleton, Nai Kui Liu, Hui Shao, Q. I.Lin Cao, Xiao Ming Xu

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

After the initial mechanical insult of spinal cord injury (SCI), secondary mediators propagate a massive loss of oligodendrocytes. We previously showed that following SCI both the total phospholipase activity and cytosolic PLA 2-IVα protein expression increased. However, the expression of secreted isoforms of PLA2 (sPLA2) and their possible roles in oligodendrocyte death following SCI remained unclear. Here we report that mRNAs extracted 15 min, 4 h, 1 day, or 1 month after cervical SCI show marked upregulation of sPLA2-IIA and IIE at 4 h after injury. In contrast, SCI induced down regulation of sPLA2-X, and no change in sPLA 2-IB, IIC, V, and XIIA expression. At the lesion site, sPLA 2-IIA and IIE expression were localized to oligodendrocytes. Recombinant human sPLA2-IIA (0.01, 0.1, or 2 μM) induced a dose-dependent cytotoxicity in differentiated adult oligodendrocyte precursor cells but not primary astrocytes or Schwann cells in vitro. Most importantly, pretreatment with S3319, a sPLA2-IIA inhibitor, before a 30 min H2O2 injury (1 or 10 mM) significantly reduced oligodendrocyte cell death at 48 h. Similarly, pretreatment with S3319 before injury with IL-1β and TNFα prevented cell death and loss of oligodendrocyte processes at 72 h. Collectively, these findings suggest that sPLA2-IIA and IIE are increased following SCI, that increased sPLA2-IIA can be cytotoxic to oligodendrocytes, and that in vitro blockade of sPLA2 can create sparing of oligodendrocytes in two distinct injury models. Therefore, sPLA2-IIA may be an important mediator of oligodendrocyte death and a novel target for therapeutic intervention following SCI.

Original languageEnglish (US)
Pages (from-to)1521-1537
Number of pages17
JournalGlia
Volume57
Issue number14
DOIs
StatePublished - Nov 27 2009

Keywords

  • Astrocytes
  • Axons
  • H O
  • IL-1β
  • Neurons
  • Phospholipases A
  • Reactive oxygen species
  • TNF-α

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology

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    Titsworth, W. L., Cheng, X., Ke, Y., Deng, L., Burckardt, K. A., Pendleton, C., Liu, N. K., Shao, H., Cao, Q. I. L., & Xu, X. M. (2009). Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death. Glia, 57(14), 1521-1537. https://doi.org/10.1002/glia.20867