Cargando…

Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model

Lumbar spinal stenosis (LSS) is a major cause of chronic neuropathic back and/or leg pain. Recently, we demonstrated that a significant number of macrophages infiltrated into the cauda equina after compression injury, causing neuroinflammation, and consequently mediating neuropathic pain development...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Jeeyoun, Choi, Haeyoung, Park, Chansol, Jeon, Sangryong, Yune, Taeyoung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707917/
https://www.ncbi.nlm.nih.gov/pubmed/34948220
http://dx.doi.org/10.3390/ijms222413426
_version_ 1784622555300102144
author Lee, Jeeyoun
Choi, Haeyoung
Park, Chansol
Jeon, Sangryong
Yune, Taeyoung
author_facet Lee, Jeeyoun
Choi, Haeyoung
Park, Chansol
Jeon, Sangryong
Yune, Taeyoung
author_sort Lee, Jeeyoun
collection PubMed
description Lumbar spinal stenosis (LSS) is a major cause of chronic neuropathic back and/or leg pain. Recently, we demonstrated that a significant number of macrophages infiltrated into the cauda equina after compression injury, causing neuroinflammation, and consequently mediating neuropathic pain development and/or maintenance. However, the molecular mechanisms underlying macrophage infiltration and activation have not been elucidated. Here, we demonstrated the critical role of histone H3K27 demethylase Jmjd3 in blood-nerve barrier dysfunction following macrophage infiltration and activation in LSS rats. The LSS rat model was induced by cauda equina compression using a silicone block within the epidural spaces of the L5-L6 vertebrae with neuropathic pain developing 4 weeks after compression. We found that Jmjd3 was induced in the blood vessels and infiltrated macrophages in a rat model of neuropathic pain. The blood-nerve barrier permeability in the cauda equina was increased after compression and significantly attenuated by the Jmjd3 demethylase inhibitor, GSK-J4. GSK-J4 also inhibited the expression and activation of MMP-2 and MMP-9 and significantly alleviated the loss of tight junction proteins and macrophage infiltration. Furthermore, the activation of a macrophage cell line, RAW 264.7, by LPS was significantly alleviated by GSK-J4. Finally, GSK-J4 and a potential Jmjd3 inhibitor, gallic acid, significantly inhibited mechanical allodynia in LSS rats. Thus, our findings suggest that Jmjd3 mediates neuropathic pain development and maintenance by inducing macrophage infiltration and activation after cauda equina compression and thus may serve as a potential therapeutic target for LSS-induced neuropathic pain.
format Online
Article
Text
id pubmed-8707917
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-87079172021-12-25 Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model Lee, Jeeyoun Choi, Haeyoung Park, Chansol Jeon, Sangryong Yune, Taeyoung Int J Mol Sci Article Lumbar spinal stenosis (LSS) is a major cause of chronic neuropathic back and/or leg pain. Recently, we demonstrated that a significant number of macrophages infiltrated into the cauda equina after compression injury, causing neuroinflammation, and consequently mediating neuropathic pain development and/or maintenance. However, the molecular mechanisms underlying macrophage infiltration and activation have not been elucidated. Here, we demonstrated the critical role of histone H3K27 demethylase Jmjd3 in blood-nerve barrier dysfunction following macrophage infiltration and activation in LSS rats. The LSS rat model was induced by cauda equina compression using a silicone block within the epidural spaces of the L5-L6 vertebrae with neuropathic pain developing 4 weeks after compression. We found that Jmjd3 was induced in the blood vessels and infiltrated macrophages in a rat model of neuropathic pain. The blood-nerve barrier permeability in the cauda equina was increased after compression and significantly attenuated by the Jmjd3 demethylase inhibitor, GSK-J4. GSK-J4 also inhibited the expression and activation of MMP-2 and MMP-9 and significantly alleviated the loss of tight junction proteins and macrophage infiltration. Furthermore, the activation of a macrophage cell line, RAW 264.7, by LPS was significantly alleviated by GSK-J4. Finally, GSK-J4 and a potential Jmjd3 inhibitor, gallic acid, significantly inhibited mechanical allodynia in LSS rats. Thus, our findings suggest that Jmjd3 mediates neuropathic pain development and maintenance by inducing macrophage infiltration and activation after cauda equina compression and thus may serve as a potential therapeutic target for LSS-induced neuropathic pain. MDPI 2021-12-14 /pmc/articles/PMC8707917/ /pubmed/34948220 http://dx.doi.org/10.3390/ijms222413426 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Jeeyoun
Choi, Haeyoung
Park, Chansol
Jeon, Sangryong
Yune, Taeyoung
Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model
title Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model
title_full Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model
title_fullStr Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model
title_full_unstemmed Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model
title_short Jmjd3 Mediates Neuropathic Pain by Inducing Macrophage Infiltration and Activation in Lumbar Spinal Stenosis Animal Model
title_sort jmjd3 mediates neuropathic pain by inducing macrophage infiltration and activation in lumbar spinal stenosis animal model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707917/
https://www.ncbi.nlm.nih.gov/pubmed/34948220
http://dx.doi.org/10.3390/ijms222413426
work_keys_str_mv AT leejeeyoun jmjd3mediatesneuropathicpainbyinducingmacrophageinfiltrationandactivationinlumbarspinalstenosisanimalmodel
AT choihaeyoung jmjd3mediatesneuropathicpainbyinducingmacrophageinfiltrationandactivationinlumbarspinalstenosisanimalmodel
AT parkchansol jmjd3mediatesneuropathicpainbyinducingmacrophageinfiltrationandactivationinlumbarspinalstenosisanimalmodel
AT jeonsangryong jmjd3mediatesneuropathicpainbyinducingmacrophageinfiltrationandactivationinlumbarspinalstenosisanimalmodel
AT yunetaeyoung jmjd3mediatesneuropathicpainbyinducingmacrophageinfiltrationandactivationinlumbarspinalstenosisanimalmodel