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, Naikui Liu, Hui Shao, Q. I Lin Cao, Xiao-Ming Xu

Research output: Contribution to journalArticle

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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
Pages (from-to)1521-1537
Number of pages17
JournalGLIA
Volume57
Issue number14
DOIs
StatePublished - 2009

Fingerprint

Oligodendroglia
Spinal Cord Injuries
Protein Isoforms
Wounds and Injuries
Group IB Phospholipases A2
Group IV Phospholipases A2
Cell Death
Group II Phospholipases A2
Phospholipases
Schwann Cells
Interleukin-1
Astrocytes
Up-Regulation
Down-Regulation
Messenger RNA

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death. / Titsworth, W. Lee; Cheng, Xiaoxin; Ke, Yan; Deng, Lingxiao; Burckardt, Kenneth A.; Pendleton, Chris; Liu, Naikui; Shao, Hui; Cao, Q. I Lin; Xu, Xiao-Ming.

In: GLIA, Vol. 57, No. 14, 2009, p. 1521-1537.

Research output: Contribution to journalArticle

Titsworth, WL, Cheng, X, Ke, Y, Deng, L, Burckardt, KA, Pendleton, C, Liu, N, Shao, H, Cao, QIL & Xu, X-M 2009, 'Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death', GLIA, vol. 57, no. 14, pp. 1521-1537. https://doi.org/10.1002/glia.20867
Titsworth, W. Lee ; Cheng, Xiaoxin ; Ke, Yan ; Deng, Lingxiao ; Burckardt, Kenneth A. ; Pendleton, Chris ; Liu, Naikui ; Shao, Hui ; Cao, Q. I Lin ; Xu, Xiao-Ming. / Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death. In: GLIA. 2009 ; Vol. 57, No. 14. pp. 1521-1537.
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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.",
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AU - Cheng, Xiaoxin

AU - Ke, Yan

AU - Deng, Lingxiao

AU - Burckardt, Kenneth A.

AU - Pendleton, Chris

AU - Liu, Naikui

AU - Shao, Hui

AU - Cao, Q. I Lin

AU - Xu, Xiao-Ming

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