Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination
Document Type
Article
Publication Date
10-16-2021
Abstract
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-alpha TNF alpha]) expression and secretion were observed in vitro following PBA treatment. PBA treatment also affected the transient changes in nuclear factor kappa B (NF kappa B)-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 NF kappa B-p65 and HDAC3 in SCs in vitro.
Keywords
Inflammation, HDAC inhibitor, Peripheral nerve injury, Schwann cells, Regeneration and myelination
Divisions
fac_med
Funders
Ministry of Science, ICT & Future Planning, Republic of Korea[MOST 109-2311-B-006-005],National Health Research Institutes - Taiwan[NHRI-EX110-10925EI]
Publication Title
Journal of Neuroinflammation
Volume
18
Issue
1
Publisher
BMC
Publisher Location
CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND