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The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain
BACKGROUND: Neuropathic pain (NP) is known to be highly correlated with microglial polarization, of which the regulatory mechanism remains to be elucidated. Here, the aim of this study is to further investigate the relationship between bone morphogenetic protein 4 (BMP4) and microglial polarization...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9078433/ https://www.ncbi.nlm.nih.gov/pubmed/35535051 http://dx.doi.org/10.2147/JIR.S356531 |
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author | Liu, Changqing Sun, Qi Xu, Junmei Shen, Weiyun Li, Hui Yang, Lin |
author_facet | Liu, Changqing Sun, Qi Xu, Junmei Shen, Weiyun Li, Hui Yang, Lin |
author_sort | Liu, Changqing |
collection | PubMed |
description | BACKGROUND: Neuropathic pain (NP) is known to be highly correlated with microglial polarization, of which the regulatory mechanism remains to be elucidated. Here, the aim of this study is to further investigate the relationship between bone morphogenetic protein 4 (BMP4) and microglial polarization in the process of NP. METHODS: Firstly, normal adult rats received intrathecal BMP4 administration to assess BMP4ʹs effect on microglial polarization. Secondly, a BMP4 antagonist – Noggin – was applied to a rat NP model achieved by L5 spinal nerve ligation (SNL) to investigate whether antagonizing BMP4 signaling could alleviate allodynia by reversing the imbalance of the M1/M2 polarization ratio. In both experiments, Von-Frey filaments were used to test the changes in the paw withdrawal threshold (PWT), and Western blotting, immuno-fluorescence, PCR and flow cytometry were further performed to investigate microglial activity and the expression patterns of M1 and M2 markers, respectively. RESULTS: Firstly, BMP4 administration induced a significant PWT decrease and microglial activation in normal rats; Western blotting, PCR and flow cytometry further revealed that M1 markers including CD16, MHCII, and TNF-α showed a marked elevation after BMP4 application; while M2 markers, such as Arg-1, CD204 and IL-4, peaked at an early stage (P1 or P4) and then fell to the Sham level on P7, leading to a persistent imbalance of the M1/M2 ratio throughout the 1st week. Secondly, Noggin treatment significantly relieved allodynia and microglial activation in SNL rats. Moreover, Noggin persistently downregulated the M1 marker levels and simultaneously induced a late-stage elevation of M2 markers expressions, thereby reversing the imbalance of the M1/M2 polarization ratio. CONCLUSION: Our results indicate that BMP4 has the ability to induce microglial polarization. Antagonizing BMP4 signaling can relieve pain behavior via mitigating microglial activation and reversing the imbalance of the M1/M2 polarization ratio in the process of NP. |
format | Online Article Text |
id | pubmed-9078433 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-90784332022-05-08 The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain Liu, Changqing Sun, Qi Xu, Junmei Shen, Weiyun Li, Hui Yang, Lin J Inflamm Res Original Research BACKGROUND: Neuropathic pain (NP) is known to be highly correlated with microglial polarization, of which the regulatory mechanism remains to be elucidated. Here, the aim of this study is to further investigate the relationship between bone morphogenetic protein 4 (BMP4) and microglial polarization in the process of NP. METHODS: Firstly, normal adult rats received intrathecal BMP4 administration to assess BMP4ʹs effect on microglial polarization. Secondly, a BMP4 antagonist – Noggin – was applied to a rat NP model achieved by L5 spinal nerve ligation (SNL) to investigate whether antagonizing BMP4 signaling could alleviate allodynia by reversing the imbalance of the M1/M2 polarization ratio. In both experiments, Von-Frey filaments were used to test the changes in the paw withdrawal threshold (PWT), and Western blotting, immuno-fluorescence, PCR and flow cytometry were further performed to investigate microglial activity and the expression patterns of M1 and M2 markers, respectively. RESULTS: Firstly, BMP4 administration induced a significant PWT decrease and microglial activation in normal rats; Western blotting, PCR and flow cytometry further revealed that M1 markers including CD16, MHCII, and TNF-α showed a marked elevation after BMP4 application; while M2 markers, such as Arg-1, CD204 and IL-4, peaked at an early stage (P1 or P4) and then fell to the Sham level on P7, leading to a persistent imbalance of the M1/M2 ratio throughout the 1st week. Secondly, Noggin treatment significantly relieved allodynia and microglial activation in SNL rats. Moreover, Noggin persistently downregulated the M1 marker levels and simultaneously induced a late-stage elevation of M2 markers expressions, thereby reversing the imbalance of the M1/M2 polarization ratio. CONCLUSION: Our results indicate that BMP4 has the ability to induce microglial polarization. Antagonizing BMP4 signaling can relieve pain behavior via mitigating microglial activation and reversing the imbalance of the M1/M2 polarization ratio in the process of NP. Dove 2022-05-03 /pmc/articles/PMC9078433/ /pubmed/35535051 http://dx.doi.org/10.2147/JIR.S356531 Text en © 2022 Liu et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Liu, Changqing Sun, Qi Xu, Junmei Shen, Weiyun Li, Hui Yang, Lin The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain |
title | The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain |
title_full | The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain |
title_fullStr | The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain |
title_full_unstemmed | The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain |
title_short | The Role of Bone Morphogenetic Protein 4 in Microglial Polarization in the Process of Neuropathic Pain |
title_sort | role of bone morphogenetic protein 4 in microglial polarization in the process of neuropathic pain |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9078433/ https://www.ncbi.nlm.nih.gov/pubmed/35535051 http://dx.doi.org/10.2147/JIR.S356531 |
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