Expression and role of placental growth factor (plgf) in the inflammatory context resulting from nerve injury, the Wallerian degeneration

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Expression and role of placental growth factor (PLGF) in the inflammatory context resulting from nerve injury, the Wallerian degeneration.

Linda Chaballe1, Murielle Wouters1, Maxime Sempels1, Lieve Moons2, Peter Carmeliet3, Jean Schoenen1, Rachelle Franzen1.

1Research Centre for Cellular and Molecular Neurobiology, research unit on cephalic pain and axonal regeneration, University of Liège, Liège, Belgium.

2Laboratory of Neural Circuit Development and Regeneration, Zoological Institute K.U.Leuven, Belgium.

3The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium.

Wallerian degeneration (WD) is an inflammatory process of axonal degeneration. It includes axonal fragmentation, myelin breakdown and debris clearance by Schwann cells and macrophages, providing a favourable environment to successful axonal regeneration after nerve injury.

Placental growth factor (PLGF) is a glycoprotein of the VEGF (Vascular Endothelial Growth Factor) family. Originally identified in the placenta, it has also been detected in other organs, especially when cells are activated or stressed. In addition to its pro-angiogenic action, PLGF has various properties like monocyte activation and attraction, ability to increase expression of pro-inflammatory cytokines and chemokines, as well as axonal guidance that could make it a candidate involved in the WD process, and in the success of axonal regeneration.

To investigate this hypothesis, we first assessed PLGF expression in normal and injured adult mouse sciatic nerve. We further considered its potential role in the post-traumatic inflammatory processes, by comparing the WD events in wild-type adult mice versus transgenic adult knock-out Pgf -/- mice, in a model of sciatic nerve section.

We show that PLGF is expressed by axons in the normal adult mouse sciatic nerve. Early after injury, PLGF is only detected in Schwann cells which also express the marker p75NGFr. At further post-injury delays, PLGF is again detected in regenerated axons, while its expression in Schwann cells decreases. We also demonstrate that in absence of PLGF, Wallerian degeneration events, like macrophage invasion, Schwann cell dedifferentiation, myelin sheath degradation as well as axonal regeneration are delayed in Pgf-/- mice compared to wild-type mice.

These results strongly support our hypothesis of PLGF playing a role in the inflammatory process of WD. Further work will focus on various cytokines whose expression is influenced by PLGF and known to play a role in WD.

This work is supported by a grant from the National Funds for Scientific Research, Belgium; the Charcot Foundation in Belgium as well as the "Leon Frederciq" foundation from the University of Liege, Belgium.
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