Recombinant Slit2 suppresses neuroinflammation and Cdc42-mediated brain infiltration of peripheral immune cells via Robo1-srGAP1 pathway in a rat model of germinal matrix hemorrhage.
Apoptosis
Germinal matrix hemorrhage
Neuroinflammation
Rat
Robo1–srGAP1
Slit2
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
29 Oct 2023
29 Oct 2023
Historique:
received:
22
03
2023
accepted:
17
10
2023
medline:
31
10
2023
pubmed:
30
10
2023
entrez:
30
10
2023
Statut:
epublish
Résumé
Germinal matrix hemorrhage (GMH) is a devastating neonatal stroke, in which neuroinflammation is a critical pathological contributor. Slit2, a secreted extracellular matrix protein, plays a repulsive role in axon guidance and leukocyte chemotaxis via the roundabout1 (Robo1) receptor. This study aimed to explore effects of recombinant Slit2 on neuroinflammation and the underlying mechanism in a rat model of GMH. GMH was induced by stereotactically infusing 0.3 U of bacterial collagenase into the germinal matrix of 7-day-old Sprague Dawley rats. Recombinant Slit2 or its vehicle was administered intranasally at 1 h after GMH and daily for 3 consecutive days. A decoy receptor recombinant Robo1 was co-administered with recombinant Slit2 after GMH. Slit2 siRNA, srGAP1 siRNA or the scrambled sequences were administered intracerebroventricularly 24 h before GMH. Neurobehavior, brain water content, Western blotting, immunofluorescence staining and Cdc42 activity assays were performed. The endogenous brain Slit2 and Robo1 expressions were increased after GMH. Robo1 was expressed on neuron, astrocytes and infiltrated peripheral immune cells in the brain. Endogenous Slit2 knockdown by Slit2 siRNA exacerbated brain edema and neurological deficits following GMH. Recombinant Slit2 (rSlit2) reduced neurological deficits, proinflammatory cytokines, intercellular adhesion molecules, peripheral immune cell markers, neuronal apoptosis and Cdc42 activity in the brain tissue after GMH. The anti-neuroinflammation effects were reversed by recombinant Robo1 co-administration or srGAP1 siRNA. Recombinant Slit2 reduced neuroinflammation and neuron apoptosis after GMH. Its anti-neuroinflammation effects by suppressing onCdc42-mediated brain peripheral immune cells infiltration was at least in part via Robo1-srGAP1 pathway. These results imply that recombinant Slit2 may have potentials as a therapeutic option for neonatal brain injuries.
Sections du résumé
BACKGROUND
BACKGROUND
Germinal matrix hemorrhage (GMH) is a devastating neonatal stroke, in which neuroinflammation is a critical pathological contributor. Slit2, a secreted extracellular matrix protein, plays a repulsive role in axon guidance and leukocyte chemotaxis via the roundabout1 (Robo1) receptor. This study aimed to explore effects of recombinant Slit2 on neuroinflammation and the underlying mechanism in a rat model of GMH.
METHODS
METHODS
GMH was induced by stereotactically infusing 0.3 U of bacterial collagenase into the germinal matrix of 7-day-old Sprague Dawley rats. Recombinant Slit2 or its vehicle was administered intranasally at 1 h after GMH and daily for 3 consecutive days. A decoy receptor recombinant Robo1 was co-administered with recombinant Slit2 after GMH. Slit2 siRNA, srGAP1 siRNA or the scrambled sequences were administered intracerebroventricularly 24 h before GMH. Neurobehavior, brain water content, Western blotting, immunofluorescence staining and Cdc42 activity assays were performed.
RESULTS
RESULTS
The endogenous brain Slit2 and Robo1 expressions were increased after GMH. Robo1 was expressed on neuron, astrocytes and infiltrated peripheral immune cells in the brain. Endogenous Slit2 knockdown by Slit2 siRNA exacerbated brain edema and neurological deficits following GMH. Recombinant Slit2 (rSlit2) reduced neurological deficits, proinflammatory cytokines, intercellular adhesion molecules, peripheral immune cell markers, neuronal apoptosis and Cdc42 activity in the brain tissue after GMH. The anti-neuroinflammation effects were reversed by recombinant Robo1 co-administration or srGAP1 siRNA.
CONCLUSIONS
CONCLUSIONS
Recombinant Slit2 reduced neuroinflammation and neuron apoptosis after GMH. Its anti-neuroinflammation effects by suppressing onCdc42-mediated brain peripheral immune cells infiltration was at least in part via Robo1-srGAP1 pathway. These results imply that recombinant Slit2 may have potentials as a therapeutic option for neonatal brain injuries.
Identifiants
pubmed: 37899442
doi: 10.1186/s12974-023-02935-2
pii: 10.1186/s12974-023-02935-2
pmc: PMC10613398
doi:
Substances chimiques
Nerve Tissue Proteins
0
Receptors, Immunologic
0
RNA, Small Interfering
0
srGAP1 protein, rat
0
GTPase-Activating Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
249Subventions
Organisme : Natural Science Foundation
ID : 81901527
Organisme : National Institute of Neurological Diseases and Stroke
ID : R01-NS078755
Informations de copyright
© 2023. The Author(s).
Références
J Neuroimmune Pharmacol. 2015 Dec;10(4):576-86
pubmed: 25946986
Lab Invest. 2014 Jul;94(7):766-76
pubmed: 24840330
J Cereb Blood Flow Metab. 2022 Sep;42(9):1632-1649
pubmed: 35491813
Prog Neurobiol. 2014 Apr;115:25-44
pubmed: 24291544
J Neuroinflammation. 2020 May 16;17(1):158
pubmed: 32416727
Sci Rep. 2020 May 15;10(1):8115
pubmed: 32415164
Dev Neurobiol. 2021 Jan;81(1):3-21
pubmed: 33191581
Pediatr Nephrol. 2015 Apr;30(4):561-6
pubmed: 24777535
Sci Rep. 2020 Nov 20;10(1):20280
pubmed: 33219247
J Vis Exp. 2013 May 29;(75):e2609
pubmed: 23748408
Nat Commun. 2015 Apr 23;6:6887
pubmed: 25904499
Biochem J. 2014 Jul 1;461(1):61-73
pubmed: 24673457
ESC Heart Fail. 2021 Feb;8(1):447-460
pubmed: 33236535
Neuropharmacology. 2019 Nov 1;158:107727
pubmed: 31356825
J Immunol. 2019 Jan 1;202(1):239-248
pubmed: 30510066
Fluids Barriers CNS. 2022 Apr 1;19(1):28
pubmed: 35365172
Neurobiol Dis. 2016 Jan;85:164-173
pubmed: 26550694
J Am Soc Nephrol. 2016 Sep;27(9):2609-15
pubmed: 26869008
Brain Res Dev Brain Res. 1997 May 20;100(1):22-8
pubmed: 9174242
Int J Mol Sci. 2018 Jun 20;19(6):
pubmed: 29925821
Front Cell Dev Biol. 2020 Sep 16;8:571258
pubmed: 33043002
Int J Mol Sci. 2021 Aug 11;22(16):
pubmed: 34445350
Front Neurosci. 2021 May 17;15:653470
pubmed: 34079435
Exp Neurol. 2007 Oct;207(2):186-94
pubmed: 17714707
Sci Transl Med. 2010 Mar 17;2(23):23ra19
pubmed: 20375003
J Neurosci. 2014 Apr 16;34(16):5717-31
pubmed: 24741061
Cardiovasc Toxicol. 2021 Dec;21(12):973-983
pubmed: 34410632
CNS Neurosci Ther. 2021 Jan;27(1):36-47
pubmed: 33381913
Angiogenesis. 2008;11(1):13-21
pubmed: 18264786
Mol Cell Biol. 2011 Feb;31(3):404-16
pubmed: 21135133
Stroke. 2011 Jun;42(6):1781-6
pubmed: 21527759
PLoS One. 2018 Jun 4;13(6):e0198508
pubmed: 29864155
Neurotherapeutics. 2016 Oct;13(4):661-670
pubmed: 27730544
Nat Rev Neurol. 2021 Apr;17(4):199-214
pubmed: 33504979
Exp Neurol. 2012 Jul;236(1):69-78
pubmed: 22524990
Stroke. 2022 Jun;53(6):2058-2068
pubmed: 35514286
Int Immunopharmacol. 2013 Dec;17(4):1218-25
pubmed: 23827753
Neurobiol Dis. 2013 Jun;54:24-31
pubmed: 23473743
Brain Behav Immun. 2019 Jul;79:174-185
pubmed: 30711510
Neuro Oncol. 2009 Dec;11(6):779-89
pubmed: 20008733
Brain Pathol. 2023 Mar;33(2):e13106
pubmed: 35762501
J Leukoc Biol. 2007 Sep;82(3):465-76
pubmed: 17565045
J Leukoc Biol. 2009 Dec;86(6):1403-15
pubmed: 19759280
J Cereb Blood Flow Metab. 2020 Sep;40(9):1752-1768
pubmed: 32423330
J Immunol. 2010 Nov 15;185(10):6294-305
pubmed: 20944010
Angiogenesis. 2018 May;21(2):237-249
pubmed: 29299781
Sci Rep. 2020 Sep 24;10(1):15676
pubmed: 32973238
Cancer Res. 2014 Mar 1;74(5):1529-40
pubmed: 24448236
Biomed Pharmacother. 2022 May;149:112797
pubmed: 35279596
Biochem Biophys Res Commun. 2019 Jun 30;514(3):868-874
pubmed: 31084928
Stroke. 2022 May;53(5):1473-1486
pubmed: 35387495
J Cereb Blood Flow Metab. 2020 Oct;40(10):2026-2037
pubmed: 31648593
Nat Immunol. 2020 Dec;21(12):1496-1505
pubmed: 33106668
Int J Lab Hematol. 2017 Jun;39(3):e70-e73
pubmed: 28004534
J Immunol. 2014 Jan 1;192(1):385-93
pubmed: 24272999
Cell Death Dis. 2019 Jul 19;10(8):555
pubmed: 31324751
Expert Opin Ther Targets. 2020 Aug;24(8):805-818
pubmed: 32378435
Blood Cells Mol Dis. 2019 May;76:7-12
pubmed: 30846360
Exp Ther Med. 2021 Sep;22(3):1042
pubmed: 34373728