Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Jeremy Tsung-Chieh, Schmidt, Lea, Schürger, Christina, Hankir, Mohammed K., Krug, Susanne M., Rittner, Heike L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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
_version_ 1784573189394792448
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
work_keys_str_mv AT chenjeremytsungchieh netrin1asamultitargetbarrierstabilizerintheperipheralnerveafterinjury
AT schmidtlea netrin1asamultitargetbarrierstabilizerintheperipheralnerveafterinjury
AT schurgerchristina netrin1asamultitargetbarrierstabilizerintheperipheralnerveafterinjury
AT hankirmohammedk netrin1asamultitargetbarrierstabilizerintheperipheralnerveafterinjury
AT krugsusannem netrin1asamultitargetbarrierstabilizerintheperipheralnerveafterinjury
AT rittnerheikel netrin1asamultitargetbarrierstabilizerintheperipheralnerveafterinjury