{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:05:08Z","timestamp":1776272708081,"version":"3.50.1"},"reference-count":75,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,7,11]],"date-time":"2016-07-11T00:00:00Z","timestamp":1468195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01\u2010AR\u2010060605"],"award-info":[{"award-number":["R01\u2010AR\u2010060605"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Blood\u2013brain barrier (<jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content>) 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, <jats:styled-content style=\"fixed-case\">MRL<\/jats:styled-content>\/<jats:italic>lpr<\/jats:italic> mice and the <jats:styled-content style=\"fixed-case\">MRL<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MpJ<\/jats:styled-content> 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 <jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content> integrity. Complement activation occurs in lupus resulting in increased generation of circulating C5a, which caused the endothelial layer to become \u2018leaky\u2019. In this study, we show that C5a and lupus serum induced apoptosis in cultured human brain microvascular endothelial cells (<jats:styled-content style=\"fixed-case\">HBMVEC<\/jats:styled-content>s), whereas selective C5a receptor 1 (C5aR1) antagonist reduced apoptosis in these cells, demonstrating C5a\/C5aR1\u2010dependence. Gene expression of initiator caspases, caspase 1 and caspase 8, and pro\u2010apoptotic proteins death\u2010associated protein kinase 1, Fas\u2010associated protein (<jats:styled-content style=\"fixed-case\">FADD<\/jats:styled-content>), cell death\u2010inducing DNA fragmentation factor 45 000 MW subunit A\u2010like effector B (<jats:styled-content style=\"fixed-case\">CIDEB<\/jats:styled-content>) and BCL2\u2010associated X protein were increased in <jats:styled-content style=\"fixed-case\">HBMVEC<\/jats:styled-content>s 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 <jats:styled-content style=\"fixed-case\">FADD<\/jats:styled-content>, caspase 8\/3 and <jats:styled-content style=\"fixed-case\">CIDEB<\/jats:styled-content> 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 <jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content> alterations and preserve the physiological function of BBB in central nervous system lupus.<\/jats:p>","DOI":"10.1111\/imm.12619","type":"journal-article","created":{"date-parts":[[2016,5,24]],"date-time":"2016-05-24T10:12:43Z","timestamp":1464084763000},"page":"407-419","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["C5a induces caspase\u2010dependent apoptosis in brain vascular endothelial cells in experimental lupus"],"prefix":"10.1111","volume":"148","author":[{"given":"Supriya D.","family":"Mahajan","sequence":"first","affiliation":[{"name":"Department of Medicine University at Buffalo Buffalo NY 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