Blood-brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses
Blood-brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses
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DOI：
10.1073/pnas.2021915118
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发表时间：
2021-05-04
影响因子：
11.1
通讯作者：
Frank, Joseph A.
中科院分区：
文献类型：
--
作者：
Burks, Scott R.;Kersch, Cymon N.;Frank, Joseph A.
颈动脉内高渗甘露醇血？脑屏障破坏（BBBD）对于递送中枢神经系统恶性肿瘤的治疗剂是有效且安全的。ICAHM可诱导改变内皮细胞和紧密连接完整性以实现BBBD。然而，神经炎症的发生后，半球BBBD ICAHM仍然未知。ICAHM后大鼠大脑中的时间蛋白质组学变化包括损伤相关分子模式、细胞因子、趋化因子、营养因子和细胞粘附分子的增加，表明无菌炎症反应（SIR）。蛋白质组学变化发生在ICAHM输注后5 min内，并在96 h时恢复至基线水平。ICAHM BBBD后的转录组学分析进一步支持SIR。免疫组化显示活化的星形胶质细胞、小胶质细胞和巨噬细胞。此外，血清中促炎蛋白升高，对侧半球的蛋白质组学和组织学结果显示SIR不太明显，表明ICAHM输注区域以外的神经炎症。总的来说，这些结果表明ICAHM诱导了一种短暂的SIR，这种SIR可能被用于神经免疫调节。
Intracarotid arterial hyperosmolar mannitol (ICAHM) blood?brain barrier disruption (BBBD) is effective and safe for delivery of therapeutics for central nervous system malignancies. ICAHM osmotically alters endothelial cells and tight junction integrity to achieve BBBD. However, occurrence of neuroinflammation following hemispheric BBBD by ICAHM remains unknown. Temporal proteomic changes in rat brains following ICAHM included increased damage-associated molecular patterns, cytokines, chemokines, trophic factors, and cell adhesion molecules, indicative of a sterile inflammatory response (SIR). Proteomic changes occurred within 5 min of ICAHM infusion and returned to baseline by 96 h. Transcriptomic analyses following ICAHM BBBD further supported an SIR. Immunohistochemistry revealed activated astrocytes, microglia, and macrophages. Moreover, proinflammatory proteins were elevated in serum, and proteomic and histological findings from the contralateral hemisphere demonstrated a less pronounced SIR, suggesting neuroinflammation beyond regions of ICAHM infusion. Collectively, these results demonstrate ICAHM induces a transient SIR that could potentially be harnessed for neuroimmunomodulation.