C5a induces caspase-dependent apoptosis in brain vascular endothelial cells in experimental lupus

Mahajan, Supriya D., Tutino, Vincent M., Redae, Yonas, Meng, Hui, Siddiqui, Adnan, Woodruff, Trent M., Jarvis, James N., Hennon, Teresa, Schwartz, Stanley, Quigg, Richard J. and Alexander, Jessy J. (2016) C5a induces caspase-dependent apoptosis in brain vascular endothelial cells in experimental lupus. Immunology, 148 4: 407-419. doi:10.1111/imm.12619

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Author Mahajan, Supriya D.
Tutino, Vincent M.
Redae, Yonas
Meng, Hui
Siddiqui, Adnan
Woodruff, Trent M.
Jarvis, James N.
Hennon, Teresa
Schwartz, Stanley
Quigg, Richard J.
Alexander, Jessy J.
Title C5a induces caspase-dependent apoptosis in brain vascular endothelial cells in experimental lupus
Journal name Immunology   Check publisher's open access policy
ISSN 1365-2567
0019-2805
Publication date 2016-08-01
Sub-type Article (original research)
DOI 10.1111/imm.12619
Open Access Status File (Author Post-print)
Volume 148
Issue 4
Start page 407
End page 419
Total pages 13
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Language eng
Formatted abstract
Blood–brain barrier (BBB) dysfunction complicates central nervous system lupus, an important aspect of systemic lupus erythematosus. To gain insight into the underlying mechanism, vascular corrosion casts of brain were generated from the lupus mouse model, MRL/lpr mice and the MRL/MpJ congenic controls. Scanning electron microscopy of the casts showed loss of vascular endothelial cells in lupus mice compared with controls. Immunostaining revealed a significant increase in caspase 3 expression in the brain vascular endothelial cells, which suggests that apoptosis could be an important mechanism causing cell loss, and thereby loss of BBB integrity. Complement activation occurs in lupus resulting in increased generation of circulating C5a, which caused the endothelial layer to become ‘leaky’. In this study, we show that C5a and lupus serum induced apoptosis in cultured human brain microvascular endothelial cells (HBMVECs), whereas selective C5a receptor 1 (C5aR1) antagonist reduced apoptosis in these cells, demonstrating C5a/C5aR1-dependence. Gene expression of initiator caspases, caspase 1 and caspase 8, and pro-apoptotic proteins death-associated protein kinase 1, Fas-associated protein (FADD), cell death-inducing DNA fragmentation factor 45 000 MW subunit A-like effector B (CIDEB) and BCL2-associated X protein were increased in HBMVECs treated with lupus serum or C5a, indicating that both the intrinsic and extrinsic apoptotic pathways could be critical mediators of brain endothelial cell apoptosis in this setting. Overall, our findings suggest that C5a/C5aR1 signalling induces apoptosis through activation of FADD, caspase 8/3 and CIDEB in brain endothelial cells in lupus. Further elucidation of the underlying apoptotic mechanisms mediating the reduced endothelial cell number is important in establishing the potential therapeutic effectiveness of C5aR1 inhibition that could prevent and/or reduce BBB alterations and preserve the physiological function of BBB in central nervous system lupus.
Keyword Apoptosis
Blood–brain barrier
Complement
Endothelial cells
Neurodegeneration
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Biomedical Sciences Publications
 
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