Schwann Cell Autocrine and Paracrine Regulatory Mechanisms, Mediated by Allopregnanolone and BDNF, Modulate PKCε in Peripheral Sensory Neurons.

Veronica Bonalume,Martin Schmelz,Alessandro Faroni,Lucia Caffino,Richard W Carr,Luca F Castelnovo,Fabio Fumagalli,Sheng Liu,Valerio Magnaghi,Flavio Giavarini,Donatella Caruso

doi:10.3390/cells9081874

Abstract

Protein kinase type C-ε (PKCε) plays important roles in the sensitization of primary afferent nociceptors, such as ion channel phosphorylation, that in turn promotes mechanical hyperalgesia and pain chronification. In these neurons, PKCε is modulated through the local release of mediators by the surrounding Schwann cells (SCs). The progesterone metabolite allopregnanolone (ALLO) is endogenously synthesized by SCs, whereas it has proven to be a crucial mediator of neuron-glia interaction in peripheral nerve fibers. Biomolecular and pharmacological studies on rat primary SCs and dorsal root ganglia (DRG) neuronal cultures were aimed at investigating the hypothesis that ALLO modulates neuronal PKCε, playing a role in peripheral nociception. We found that SCs tonically release ALLO, which, in turn, autocrinally upregulated the synthesis of the growth factor brain-derived neurotrophic factor (BDNF). Subsequently, glial BDNF paracrinally activates PKCε via trkB in DRG sensory neurons. Herein, we report a novel mechanism of SCs-neuron cross-talk in the peripheral nervous system, highlighting a key role of ALLO and BDNF in nociceptor sensitization. These findings emphasize promising targets for inhibiting the development and chronification of neuropathic pain.

Highlights

Schwann cells (SCs) are the main glial cells of the peripheral nervous system (PNS)
Using a combination of biomolecular and pharmacological approaches we studied rat primary SCs and dorsal root ganglia (DRG) neurons in vitro, investigating whether Protein kinase type C-ε (PKCε) in neurons is regulated by ALLO and/or other factors released by SCs
IFL images confirmed that the PKCε protein was present both in DRG neurons (Figure 1b, upper panels; images in two z-axis optical sections) and SCs (Figure 1b, lower panels); specificity was assessed by co-labeling with SMI32 and s100, markers of DRG neurons and SC, respectively

Summary

Introduction

Schwann cells (SCs) are the main glial cells of the peripheral nervous system (PNS). MyelinatingSCs form the myelin sheath, which electrically isolates axons and allows saltatory conduction ofCells 2020, 9, 1874; doi:10.3390/cells9081874 www.mdpi.com/journal/cellsCells 2020, 9, 1874 the action potentials. Schwann cells (SCs) are the main glial cells of the peripheral nervous system (PNS). SCs form the myelin sheath, which electrically isolates axons and allows saltatory conduction of. Non-myelinating SCs surround unmyelinated fibers to form Remak bundles, where SCs ensheath multiple small-caliber axons, isolating one from another [1,2]. The majority of unmyelinated axons serve sensory function associated with thermoception and nociception. Besides these structural purposes, SCs cross-interact with neurons, with whole axons, regulating their physiological functions. A plethora of mediators is produced and/or released by SCs, regulating the neuron-glial interaction, including neuropeptides, cytokines, growth factors, integrins, neuregulins, neurotransmitters and neuroactive steroids [3,4,5,6,7]

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Results

Conclusion