Abstract
In response to peripheral nerve injury, Schwann cells adopt a migratory phenotype and modify the extracellular matrix to make it permissive for cell migration and axonal re-growth. Uridine 5′-triphosphate (UTP) and other nucleotides are released during nerve injury and activate purinergic receptors expressed on the Schwann cell surface, but little is known about the involvement of purine signalling in wound healing. We studied the effect of UTP on Schwannoma cell migration and wound closure and the intracellular signaling pathways involved. We found that UTP treatment induced Schwannoma cell migration through activation of P2Y2 receptors and through the increase of extracellular matrix metalloproteinase-2 (MMP-2) activation and expression. Knockdown P2Y2 receptor or MMP-2 expression greatly reduced wound closure and MMP-2 activation induced by UTP. MMP-2 activation evoked by injury or UTP was also mediated by phosphorylation of all 3 major mitogen-activated protein kinases (MAPKs): JNK, ERK1/2, and p38. Inhibition of these MAPK pathways decreased both MMP-2 activation and cell migration. Interestingly, MAPK phosphorylation evoked by UTP exhibited a biphasic pattern, with an early transient phosphorylation 5 min after treatment, and a late and sustained phosphorylation that appeared at 6 h and lasted up to 24 h. Inhibition of MMP-2 activity selectively blocked the late, but not the transient, phase of MAPK activation. These results suggest that MMP-2 activation and late MAPK phosphorylation are part of a positive feedback mechanism to maintain the migratory phenotype for wound healing. In conclusion, our findings show that treatment with UTP stimulates in vitro Schwannoma cell migration and wound repair through a MMP-2-dependent mechanism via P2Y2 receptors and MAPK pathway activation.
Highlights
Peripheral nerve injury initiates a sequence of events through which macrophages and Schwann cells clear damaged axons and potentiate axonal regeneration and nerve remyelination [1]
We report that Uridine 59-triphosphate (UTP) stimulates in vitro Schwannoma cell migration and wound repair through a matrix metalloproteinases (MMPs)-2-dependent mechanism via P2Y2 receptors and mitogen-activated protein kinases (MAPKs) pathway activation
Growing evidence suggests that nucleotides that are released upon injury stimulate nucleotide P2 receptors and serve as endogenous signals to induce a rapid wound healing response in glial cells [48,49,50]
Summary
Peripheral nerve injury initiates a sequence of events through which macrophages and Schwann cells clear damaged axons and potentiate axonal regeneration and nerve remyelination [1]. During Wallerian degeneration, de-differentiating Schwann cells secrete growth factors and neurite-promoting factors to guide the growing axon, as well as proteolytic enzymes to remodel extracellular matrix (ECM) and facilitate cell migration [2,3,4,5]. MMP-9 activates the Akt/ERK pathway and promotes migration by binding to the low-density lipoprotein receptor-related protein [20]. Taking into account these findings, the modulation of MMP activity may be a relevant target to enhance regeneration in demyelinating diseases of the peripheral nervous system (PNS) [17]
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