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Discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification

Inflammation following nerve injury and surgery often causes peripheral nerve adhesion (PNA) to the surrounding tissue. Numerous investigations independently examined the prevention or inhibition of PNA, however, an intervention targeting macrophages has not been fully elucidated. Basement membrane...

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Autores principales: Li, Shengyou, Yu, Beibei, Gao, Xue, Zheng, Yi, Ma, Teng, Hao, Yiming, Wu, Haining, Wei, Bin, Wei, Yitao, Luo, Zhuojing, Xia, Bing, Huang, Jinghui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9676506/
https://www.ncbi.nlm.nih.gov/pubmed/36419629
http://dx.doi.org/10.3389/fphar.2022.1035143
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author Li, Shengyou
Yu, Beibei
Gao, Xue
Zheng, Yi
Ma, Teng
Hao, Yiming
Wu, Haining
Wei, Bin
Wei, Yitao
Luo, Zhuojing
Xia, Bing
Huang, Jinghui
author_facet Li, Shengyou
Yu, Beibei
Gao, Xue
Zheng, Yi
Ma, Teng
Hao, Yiming
Wu, Haining
Wei, Bin
Wei, Yitao
Luo, Zhuojing
Xia, Bing
Huang, Jinghui
author_sort Li, Shengyou
collection PubMed
description Inflammation following nerve injury and surgery often causes peripheral nerve adhesion (PNA) to the surrounding tissue. Numerous investigations independently examined the prevention or inhibition of PNA, however, an intervention targeting macrophages has not been fully elucidated. Basement membrane (BM) genes are known to modulate central nervous system (CNS) inflammation, however, their activities in the peripheral nervous system (PNS) remains undiscovered. In this report, we carried out weighted correlation network analysis (WCNA) to screen for principal sciatic nerve injury (SNI) module genes. Once an association between the module and BM genes was established, the protein–protein interaction (PPI) and immune infiltration analyses were employed to screen for relevant BM-related immune genes (Itgam, SDC1, Egflam, and CD44) in SNI. Subsequently, using the Drug SIGnatures (DSigDB) database and molecular docking, we demonstrated that Trichostatin A (TSA) interacted with key immune genes. TSA is known to enhance M2 macrophage expression and attenuate fibrosis. Nevertheless, the significance of the epigenetic modulation of macrophage phenotypes in dorsal root ganglion (DRG) is undetermined after SNI. In this article, we examined the TSA role in fibrogenesis and macrophage plasticity associated with DRG. We revealed that TSA enhanced M2 macrophage aggregation, inhibited fibroblast activation, and improved sciatic nerve regeneration (SNR) and sensory functional recovery (FR) after SNI. In addition, TSA suppressed M1 macrophages and enhanced M2 macrophage invasion within the DRG tissue. Furthermore, TSA dramatically reduced IL-1β and TNFα levels, while upregulating IL-10 level. In summary, this research revealed for the first time that TSA alleviates fibrosis in DRG by promoting an M1 to M2 macrophage transition, which, in turn, accelerates SNR.
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spelling pubmed-96765062022-11-22 Discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification Li, Shengyou Yu, Beibei Gao, Xue Zheng, Yi Ma, Teng Hao, Yiming Wu, Haining Wei, Bin Wei, Yitao Luo, Zhuojing Xia, Bing Huang, Jinghui Front Pharmacol Pharmacology Inflammation following nerve injury and surgery often causes peripheral nerve adhesion (PNA) to the surrounding tissue. Numerous investigations independently examined the prevention or inhibition of PNA, however, an intervention targeting macrophages has not been fully elucidated. Basement membrane (BM) genes are known to modulate central nervous system (CNS) inflammation, however, their activities in the peripheral nervous system (PNS) remains undiscovered. In this report, we carried out weighted correlation network analysis (WCNA) to screen for principal sciatic nerve injury (SNI) module genes. Once an association between the module and BM genes was established, the protein–protein interaction (PPI) and immune infiltration analyses were employed to screen for relevant BM-related immune genes (Itgam, SDC1, Egflam, and CD44) in SNI. Subsequently, using the Drug SIGnatures (DSigDB) database and molecular docking, we demonstrated that Trichostatin A (TSA) interacted with key immune genes. TSA is known to enhance M2 macrophage expression and attenuate fibrosis. Nevertheless, the significance of the epigenetic modulation of macrophage phenotypes in dorsal root ganglion (DRG) is undetermined after SNI. In this article, we examined the TSA role in fibrogenesis and macrophage plasticity associated with DRG. We revealed that TSA enhanced M2 macrophage aggregation, inhibited fibroblast activation, and improved sciatic nerve regeneration (SNR) and sensory functional recovery (FR) after SNI. In addition, TSA suppressed M1 macrophages and enhanced M2 macrophage invasion within the DRG tissue. Furthermore, TSA dramatically reduced IL-1β and TNFα levels, while upregulating IL-10 level. In summary, this research revealed for the first time that TSA alleviates fibrosis in DRG by promoting an M1 to M2 macrophage transition, which, in turn, accelerates SNR. Frontiers Media S.A. 2022-11-07 /pmc/articles/PMC9676506/ /pubmed/36419629 http://dx.doi.org/10.3389/fphar.2022.1035143 Text en Copyright © 2022 Li, Yu, Gao, Zheng, Ma, Hao, Wu, Wei, Wei, Luo, Xia and Huang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Li, Shengyou
Yu, Beibei
Gao, Xue
Zheng, Yi
Ma, Teng
Hao, Yiming
Wu, Haining
Wei, Bin
Wei, Yitao
Luo, Zhuojing
Xia, Bing
Huang, Jinghui
Discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification
title Discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification
title_full Discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification
title_fullStr Discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification
title_full_unstemmed Discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification
title_short Discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification
title_sort discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9676506/
https://www.ncbi.nlm.nih.gov/pubmed/36419629
http://dx.doi.org/10.3389/fphar.2022.1035143
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