Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
Neurosurgical Institute, Fudan University, Shanghai 200040 China.
Sci Adv. 2021 Mar 12;7(11). doi: 10.1126/sciadv.abb6260. Print 2021 Mar.
Traumatic brain injury (TBI) leads to high mortality rate. We aimed to identify the key cytokines favoring TBI repair and found that patients with TBI with a better outcome robustly increased concentrations of macrophage colony-stimulating factor, interleukin-6, and transforming growth factor-β (termed M6T) in cerebrospinal fluid or plasma. Using TBI mice, we identified that M2-like macrophage, microglia, and endothelial cell were major sources to produce M6T. Together with the in vivo tracking of mCherry+ macrophages in zebrafish models, we confirmed that M6T treatment accelerated blood-borne macrophage infiltration and polarization toward a subset of tissue repair macrophages that expressed similar genes as microglia for neuroprotection, angiogenesis and cell migration. M6T therapy in TBI mice and zebrafish improved neurological function while blocking M6T-exacerbated brain injury. Considering low concentrations of M6T in some patients with poor prognostic, M6T treatment might repair TBI via generating a previously unidentified subset of tissue repair macrophages.
创伤性脑损伤（TBI）导致高死亡率。我们旨在确定有利于 TBI 修复的关键细胞因子，发现 TBI 预后较好的患者脑脊液或血浆中巨噬细胞集落刺激因子、白细胞介素-6 和转化生长因子-β（称为 M6T）浓度明显增加。使用 TBI 小鼠，我们发现 M2 样巨噬细胞、小胶质细胞和内皮细胞是产生 M6T 的主要来源。通过在斑马鱼模型中对 mCherry+巨噬细胞进行体内追踪，我们证实 M6T 处理可加速血源性巨噬细胞浸润和向一组组织修复巨噬细胞极化，这些巨噬细胞表达与小胶质细胞相似的基因，以实现神经保护、血管生成和细胞迁移。M6T 治疗 TBI 小鼠和斑马鱼可改善神经功能，同时阻止 M6T 加重脑损伤。考虑到一些预后较差的患者 M6T 浓度较低，M6T 治疗可能通过产生以前未识别的组织修复巨噬细胞亚群来修复 TBI。
