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Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination

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 b...

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Main Authors: Yadav, Anjali, Huang, Tzu-Chieh, Chen, Szu-Han, Ramasamy, Thamil Selvee, Hsueh, Yuan-Yu, Lin, Shau-Ping, Lu, Fu-, Liu, Ya-Hsin, Wu, Chia-Ching
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Published: BMC 2021
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R Medicine
Online Access:http://eprints.um.edu.my/34294/
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spelling my.um.eprints.342942022-09-09T06:52:27Z http://eprints.um.edu.my/34294/ Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination Yadav, Anjali Huang, Tzu-Chieh Chen, Szu-Han Ramasamy, Thamil Selvee Hsueh, Yuan-Yu Lin, Shau-Ping Lu, Fu- Liu, Ya-Hsin Wu, Chia-Ching R Medicine 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. BMC 2021-10-16 Article PeerReviewed Yadav, Anjali and Huang, Tzu-Chieh and Chen, Szu-Han and Ramasamy, Thamil Selvee and Hsueh, Yuan-Yu and Lin, Shau-Ping and Lu, Fu- and Liu, Ya-Hsin and Wu, Chia-Ching (2021) Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination. Journal of Neuroinflammation, 18 (1). ISSN 1742-2094, DOI https://doi.org/10.1186/s12974-021-02273-1 <https://doi.org/10.1186/s12974-021-02273-1>. 10.1186/s12974-021-02273-1
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic R Medicine
spellingShingle R Medicine
Yadav, Anjali
Huang, Tzu-Chieh
Chen, Szu-Han
Ramasamy, Thamil Selvee
Hsueh, Yuan-Yu
Lin, Shau-Ping
Lu, Fu-
Liu, Ya-Hsin
Wu, Chia-Ching
Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination
description 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.
format Article
author Yadav, Anjali
Huang, Tzu-Chieh
Chen, Szu-Han
Ramasamy, Thamil Selvee
Hsueh, Yuan-Yu
Lin, Shau-Ping
Lu, Fu-
Liu, Ya-Hsin
Wu, Chia-Ching
author_facet Yadav, Anjali
Huang, Tzu-Chieh
Chen, Szu-Han
Ramasamy, Thamil Selvee
Hsueh, Yuan-Yu
Lin, Shau-Ping
Lu, Fu-
Liu, Ya-Hsin
Wu, Chia-Ching
author_sort Yadav, Anjali
title Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination
title_short Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination
title_full Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination
title_fullStr Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination
title_full_unstemmed Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NF kappa B to promote axonal regeneration and remyelination
title_sort sodium phenylbutyrate inhibits schwann cell inflammation via hdac and nf kappa b to promote axonal regeneration and remyelination
publisher BMC
publishDate 2021
url http://eprints.um.edu.my/34294/
_version_ 1744649170466111488
score 13.211869

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