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Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury
The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nerv...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466625/ https://www.ncbi.nlm.nih.gov/pubmed/34576252 http://dx.doi.org/10.3390/ijms221810090 |
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author | Chen, Jeremy Tsung-Chieh Schmidt, Lea Schürger, Christina Hankir, Mohammed K. Krug, Susanne M. Rittner, Heike L. |
author_facet | Chen, Jeremy Tsung-Chieh Schmidt, Lea Schürger, Christina Hankir, Mohammed K. Krug, Susanne M. Rittner, Heike L. |
author_sort | Chen, Jeremy Tsung-Chieh |
collection | PubMed |
description | The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain. |
format | Online Article Text |
id | pubmed-8466625 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84666252021-09-27 Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury Chen, Jeremy Tsung-Chieh Schmidt, Lea Schürger, Christina Hankir, Mohammed K. Krug, Susanne M. Rittner, Heike L. Int J Mol Sci Article The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain. MDPI 2021-09-18 /pmc/articles/PMC8466625/ /pubmed/34576252 http://dx.doi.org/10.3390/ijms221810090 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 Chen, Jeremy Tsung-Chieh Schmidt, Lea Schürger, Christina Hankir, Mohammed K. Krug, Susanne M. Rittner, Heike L. Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury |
title | Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury |
title_full | Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury |
title_fullStr | Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury |
title_full_unstemmed | Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury |
title_short | Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury |
title_sort | netrin-1 as a multitarget barrier stabilizer in the peripheral nerve after injury |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466625/ https://www.ncbi.nlm.nih.gov/pubmed/34576252 http://dx.doi.org/10.3390/ijms221810090 |
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