Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage

Bart J van Dijk; Joost C M Meijers; Anne T Kloek; Veronique L Knaup; Gabriel J E Rinkel; B Paul Morgan; Marije J van der Kamp; Koji Osuka; Eleonora Aronica; Ynte M Ruigrok; Diederik van de Beek; Matthijs Brouwer; Marcela Pekna; Elly M Hol; Mervyn D I Vergouwen

doi:10.1007/s12975-019-00757-0

Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage

Bart J van Dijk, Joost C M Meijers, Anne T Kloek, Veronique L Knaup, Gabriel J E Rinkel, B Paul Morgan, Marije J van der Kamp, Koji Osuka, Eleonora Aronica, Ynte M Ruigrok, Diederik van de Beek, Matthijs Brouwer, Marcela Pekna, Elly M Hol, Mervyn D I Vergouwen

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Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3-10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH.

Originele taal-2	Engels
Pagina's (van-tot)	678-688
Tijdschrift	Translational Stroke Research
Volume	11
DOI's	https://doi.org/10.1007/s12975-019-00757-0
Status	Gepubliceerd - 2020

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10.1007/s12975-019-00757-0

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van Dijk, B. J., Meijers, J. C. M., Kloek, A. T., Knaup, V. L., Rinkel, G. J. E., Morgan, B. P., van der Kamp, M. J., Osuka, K., Aronica, E., Ruigrok, Y. M., van de Beek, D., Brouwer, M., Pekna, M., Hol, E. M., & Vergouwen, M. D. I. (2020). Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage. Translational Stroke Research, 11, 678-688. https://doi.org/10.1007/s12975-019-00757-0

@article{774738f1caa94a3480a2b4e8bc01f04f,

title = "Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage",

abstract = "Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3-10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH.",

author = "{van Dijk}, {Bart J} and Meijers, {Joost C M} and Kloek, {Anne T} and Knaup, {Veronique L} and Rinkel, {Gabriel J E} and Morgan, {B Paul} and {van der Kamp}, {Marije J} and Koji Osuka and Eleonora Aronica and Ruigrok, {Ynte M} and {van de Beek}, Diederik and Matthijs Brouwer and Marcela Pekna and Hol, {Elly M} and Vergouwen, {Mervyn D I}",

year = "2020",

doi = "10.1007/s12975-019-00757-0",

language = "English",

volume = "11",

pages = "678--688",

journal = "Translational Stroke Research",

issn = "1868-4483",

publisher = "Springer",

}

TY - JOUR

T1 - Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage

AU - van Dijk, Bart J

AU - Meijers, Joost C M

AU - Kloek, Anne T

AU - Knaup, Veronique L

AU - Rinkel, Gabriel J E

AU - Morgan, B Paul

AU - van der Kamp, Marije J

AU - Osuka, Koji

AU - Aronica, Eleonora

AU - Ruigrok, Ynte M

AU - van de Beek, Diederik

AU - Brouwer, Matthijs

AU - Pekna, Marcela

AU - Hol, Elly M

AU - Vergouwen, Mervyn D I

PY - 2020

Y1 - 2020

N2 - Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3-10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH.

AB - Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3-10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH.

U2 - 10.1007/s12975-019-00757-0

DO - 10.1007/s12975-019-00757-0

M3 - Article

C2 - 31811640

SN - 1868-4483

VL - 11

SP - 678

EP - 688

JO - Translational Stroke Research

JF - Translational Stroke Research

ER -

Complement C5 Contributes to Brain Injury After Subarachnoid Hemorrhage

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