Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NFκB to promote axonal regeneration and remyelination
Journal
Journal of Neuroinflammation
Journal Volume
18
Journal Issue
1
Date Issued
2021
Author(s)
Abstract
Background: Epigenetic regulation by histone deacetylases (HDACs) in Schwann cells (SCs) after injury facilitates them to undergo de- and redifferentiation processes necessary to support various stages of nerve repair. Although de-differentiation activates the synthesis and secretion of inflammatory cytokines by SCs to initiate an immune response during nerve repair, changes in either the timing or duration of prolonged inflammation mediated by SCs can affect later processes associated with repair and regeneration. Limited studies have investigated the regulatory processes through which HDACs in SCs control inflammatory cytokines to provide a favorable environment for peripheral nerve regeneration. Methods: We employed the HDAC inhibitor (HDACi) sodium phenylbutyrate (PBA) to address this question in an in vitro RT4 SC inflammation model and an in vivo sciatic nerve transection injury model to examine the effects of HDAC inhibition on the expression of pro-inflammatory cytokines. Furthermore, we assessed the outcomes of suppression of extended inflammation on the regenerative potential of nerves by assessing axonal regeneration, remyelination, and reinnervation. Results: Significant reductions in lipopolysaccharide (LPS)-induced pro-inflammatory cytokine (tumor necrosis factor-α [TNFα]) expression and secretion were observed in vitro following PBA treatment. PBA treatment also affected the transient changes in nuclear factor κB (NFκB)-p65 phosphorylation and translocation in response to LPS induction in RT4 SCs. Similarly, PBA mediated long-term suppressive effects on HDAC3 expression and activity. PBA administration resulted in marked inhibition of pro-inflammatory cytokine secretion at the site of transection injury when compared with that in the hydrogel control group at 6-week post-injury. A conducive microenvironment for axonal regrowth and remyelination was generated by increasing expression levels of protein gene product 9.5 (PGP9.5) and myelin basic protein (MBP) in regenerating nerve tissues. PBA administration increased the relative gastrocnemius muscle weight percentage and maintained the intactness of muscle bundles when compared with those in the hydrogel control group. Conclusions: Suppressing the lengthened state of inflammation using PBA treatment favors axonal regrowth and remyelination following nerve transection injury. PBA treatment also regulates pro-inflammatory cytokine expression by inhibiting the transcriptional activation of NFκB-p65 and HDAC3 in SCs in vitro. ? 2021, The Author(s).
Subjects
HDAC inhibitor
Inflammation
Peripheral nerve injury
Regeneration and myelination
Schwann cells
4-phenylbutyric acid
arylbutyric acid derivative
axon
histone deacetylase
histone deacetylase 3
histone deacetylase inhibitor
immunoglobulin enhancer binding protein
animal
cell line
drug effect
human
inflammation
male
metabolism
nerve regeneration
pathology
physiology
rat
remyelinization
Schwann cell
sciatic neuropathy
Sprague Dawley rat
THP-1 cell line
Animals
Axons
Cell Line
Histone Deacetylase Inhibitors
Histone Deacetylases
Humans
Male
Nerve Regeneration
NF-kappa B
Phenylbutyrates
Rats
Rats, Sprague-Dawley
Remyelination
Schwann Cells
Sciatic Neuropathy
THP-1 Cells
SDGs
Type
journal article