Soluble CD146, a cerebrospinal fluid marker for neuroinflammation, promotes blood-brain barrier dysfunction

Abstract

The blood-brain barrier (BBB) dysfunction is an initial event of various neuroinflammatory diseases. However, the absence of reliable markers and mechanisms for BBB damage greatly limits the diagnosis and treatment of neuroinflammatory diseases. Soluble CD146 (sCD146) is mainly derived from vascular endothelial cells (ECs) and highly elevated in inflammatory settings. Based on a small cohort, our previous study showed that sCD146 is elevated in the cerebrospinal fluid (CSF) of multiple sclerosis (MS), which is accompanied with BBB damage. Nevertheless, whether sCD146 monitors and regulates the BBB dysfunction remains unknown.Methods: Coupled serum and CSF samples from patients with or without neuroinflammatory diseases were collected via multicenter collaborations. sCD146 was measured by sandwich ELISA using anti-CD146 antibodies AA1 and AA98, both of which were generated in our laboratory. The correlations between sCD146 and other clinical parameters or inflammatory factors were analyzed by Spearman's correlation coefficient analysis. The role of sCD146 on BBB function was examined in an in vitro BBB model.Results: Between July 20, 2011, and February 31, 2017, we collected coupled serum and CSF samples from 823 patients, of which 562 (68.3%) had neuroinflammatory diseases, 44 (5.3%) had remitting MS, and 217 (26.4%) had non-inflammatory neurological diseases (NIND). We found that sCD146 in CSF, but not in serum, is abnormally elevated in neuroinflammatory diseases (37.3 ± 13.3 ng/mL) compared with NIND (4.7 ± 2.9 ng/mL) and remitting MS (4.6 ± 3.5 ng/mL). Abnormally elevated CSF sCD146 is significantly correlated with the hyperpermeability-related clinical parameters of BBB and neuroinflammation-related factors. Moreover, CSF sCD146 shows higher sensitivity and specificity for evaluating BBB damage. Using an in vitro BBB model, we found that sCD146 impairs BBB function by promoting BBB permeability via an association with integrin αvβ1. Blocking integrin αvβ1 significantly attenuates sCD146-induced hyperpermeability of the BBB.Conclusion: Our study provides convincing evidence that CSF sCD146 is a sensitive marker of BBB damage and neuroinflammation. Furthermore, sCD146 is actively involved in BBB dysfunction.

CD146, from a melanoma cell adhesion molecule to a signaling receptor

“…[11][12][13] Soluble CD146 can be detected in cell culture supernatants, serum, and interstitial fluids from either healthy or unhealthy subjects. [14][15][16] Because sCD146 does not have either transmembrane or cytoplasmic regions, it is not competent in cellular adhesion. 17,18 Therefore, we will not describe sCD146, its ligands and its functions in this review, although it is a potential target in tumor microenvironment of CD146-positive invasive tumors.…”

Review and prospect of CD146 research

“…[350] . Mebazaa团队 [351] 发现, sCD146的表达水平与左 最近研究发现, sCD146在二尖瓣狭窄 [352] 、急性冠脉 综合征 [353] , 心衰系统性充血 [354] [357] , 其表达水平的变化可作为监测多发性硬化症等疾病进 程的指标 [358] , 评价血脑屏障损伤的程度.…”

“…2013年, Blot-Cha-baud团队 [341] 首次发现, sCD146可以作为结合内皮细 [359] . 本团队 [357] 特异识别sCD146的单克隆抗体M2J-1 [246] 以及特异识 别肿瘤细胞CD146的抗体TsCD146 [363] 的制备, 也是近 几年CD146抗体研究领域的重要突破. [224,370] .…”

“…(enzyme-linked immunosorbent assay, ELISA)检测血 清、脑脊液、滑膜液中的sCD146, 以评估血脑屏障完 整性、胚胎移植、二尖瓣吻合术预后、肾透析和心血 管风险等疾病的进展. 使用的抗体组合包括S-Endo 1/ COM7A4 [391] , AA1/AA98 [357,358,361] , Clone 128018/ SHM45 [347] , CD146蛋白/OJ79抗体(竞争抑制性ELI-SA) [356] 以及来自Uscn Life Science [346,392] , SinoBiologicals [47] 和R&D Systems公司 [393] 的三个商品化试剂盒.…”

Change of reception and lactate transport by cerebral endothelium under the influence of viral and bacterial inflammation in vitro

“…Церебральные эндотелиоциты играют важную роль в патогенезе инфекционных заболеваний центральной нервной системы (ЦНС). Эндотелиальная дисфункция считается одним из ранних событий в нарушении целостности гематоэнцефалического барьера при различных патологических состояниях [1], в частности при воспалении бактериального и вирусного генеза. Моделирование нейровсопаления in vitro позволяет изучить механизмы патогенеза эндотелиальной дисфункции и определить роль церебральных эндотелиоцитов в патогенезе повреждения гематоэнцефалического барьера.…”