Macrophage-specific RhoA knockout delays Wallerian degeneration after peripheral nerve injury in mice.
Macrophage
Nerve regeneration
Peripheral nerve injury
RhoA
Wallerian degeneration
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
15 Oct 2021
15 Oct 2021
Historique:
received:
06
06
2021
accepted:
07
10
2021
entrez:
16
10
2021
pubmed:
17
10
2021
medline:
10
2
2022
Statut:
epublish
Résumé
Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury. Immunohistochemistry, Western blotting, H&E staining, and electrophysiology were performed to access the Wallerian degeneration and axonal regeneration after sciatic nerve transection and crush injury in the Lyz 1. RhoA was specifically knocked out in macrophages of the cKO mice; 2. The segmentation of axons and myelin, the axonal regeneration, and nerve conduction in the injured nerve were significantly impeded while the myoatrophy was more severe in the cKO mice compared with those in Cre mice; 3. RhoA knockout attenuated the migration and phagocytosis of macrophages in vivo and in vitro; 4. ROCK and MLCK were downregulated in the cKO macrophages while inhibition of ROCK and MLCK could weaken the migration and phagocytosis of macrophages. Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.
Sections du résumé
BACKGROUND
BACKGROUND
Plenty of macrophages are recruited to the injured nerve to play key roles in the immunoreaction and engulf the debris of degenerated axons and myelin during Wallerian degeneration, thus creating a conducive microenvironment for nerve regeneration. Recently, drugs targeting the RhoA pathway have been widely used to promote peripheral axonal regeneration. However, the role of RhoA in macrophage during Wallerian degeneration and nerve regeneration after peripheral nerve injury is still unknown. Herein, we come up with the hypothesis that RhoA might influence Wallerian degeneration and nerve regeneration by affecting the migration and phagocytosis of macrophages after peripheral nerve injury.
METHODS
METHODS
Immunohistochemistry, Western blotting, H&E staining, and electrophysiology were performed to access the Wallerian degeneration and axonal regeneration after sciatic nerve transection and crush injury in the Lyz
RESULTS
RESULTS
1. RhoA was specifically knocked out in macrophages of the cKO mice; 2. The segmentation of axons and myelin, the axonal regeneration, and nerve conduction in the injured nerve were significantly impeded while the myoatrophy was more severe in the cKO mice compared with those in Cre mice; 3. RhoA knockout attenuated the migration and phagocytosis of macrophages in vivo and in vitro; 4. ROCK and MLCK were downregulated in the cKO macrophages while inhibition of ROCK and MLCK could weaken the migration and phagocytosis of macrophages.
CONCLUSIONS
CONCLUSIONS
Our findings suggest that RhoA depletion in macrophages exerts a detrimental effect on Wallerian degeneration and nerve regeneration, which is most likely due to the impaired migration and phagocytosis of macrophages resulted from disrupted RhoA/ROCK/MLCK pathway. Since previous research has proved RhoA inhibition in neurons was favoring for axonal regeneration, the present study reminds us of that the cellular specificity of RhoA-targeted drugs is needed to be considered in the future application for treating peripheral nerve injury.
Identifiants
pubmed: 34654444
doi: 10.1186/s12974-021-02292-y
pii: 10.1186/s12974-021-02292-y
pmc: PMC8520251
doi:
Substances chimiques
RhoA protein, mouse
EC 3.6.5.2
rhoA GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
234Subventions
Organisme : National Natural Science Foundation of China
ID : 82071386
Organisme : National Natural Science Foundation of China
ID : 81870982
Organisme : National Natural Science Foundation of China
ID : 81571182
Organisme : Key Research & Development Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory
ID : 2018GZR110104008
Organisme : Guangdong Key Laboratory of Fuel Cell Technology
ID : N201904
Organisme : Science and Technology Planning Project of Guangdong Province
ID : 2015A020212024
Organisme : National Basic Research Program of China (973 Program)
ID : 2014CB542202
Organisme : Natural Science Foundation of Guangdong Province
ID : 2017A030312009
Informations de copyright
© 2021. The Author(s).
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