Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Interdisciplinary Neuroscience Graduate Program, Arizona State University, Tempe, AZ 85281, USA.
Sci Transl Med. 2021 Apr 14;13(589). doi: 10.1126/scitranslmed.abc7029.
Acute brain injury mobilizes circulating leukocytes to transmigrate into the perivascular space and brain parenchyma. This process amplifies neural injury. Bone marrow hematopoiesis replenishes the exhausted peripheral leukocyte pools. However, it is not known whether brain injury influences the development of bone marrow lineages and how altered hematopoietic cell lineages affect neurological outcome. Here, we showed that bone marrow hematopoietic stem cells (HSCs) can be swiftly skewed toward the myeloid lineage in patients with intracerebral hemorrhage (ICH) and experimental ICH models. Lineage tracing revealed a predominantly augmented hematopoiesis of Ly6C monocytes infiltrating the ICH brain, where they generated alternatively activated macrophages and suppressed neuroinflammation and brain injury. The ICH brain uses β3-adrenergic innervation that involves cell division cycle 42 to promote bone marrow hematopoiesis of Ly6C monocytes, which could be further potentiated by the U.S. Food and Drug Administration-approved β3-adrenergic agonist mirabegron. Our results suggest that brain injury modulates HSC lineage development to curb distal brain inflammation, implicating the bone marrow as a unique niche for self-protective neuroimmune interaction that might be exploited to obtain therapeutic effects.
急性脑损伤会动员循环中的白细胞迁移到血管周围空间和脑实质中。这个过程会放大神经损伤。骨髓造血会补充耗尽的外周白细胞池。然而，目前尚不清楚脑损伤是否会影响骨髓谱系的发育，以及造血细胞谱系的改变如何影响神经功能预后。在这里，我们发现，脑出血（ICH）患者和实验性 ICH 模型中，骨髓造血干细胞（HSCs）可以迅速向髓系分化。谱系追踪显示，Ly6C 单核细胞在 ICH 大脑中的造血作用明显增强，这些细胞产生了替代性激活的巨噬细胞，抑制了神经炎症和脑损伤。ICH 大脑利用涉及细胞分裂周期蛋白 42 的β3-肾上腺素能神经支配来促进 Ly6C 单核细胞的骨髓造血，而美国食品和药物管理局批准的β3-肾上腺素能激动剂米拉贝隆可以进一步增强这种作用。我们的研究结果表明，脑损伤会调节 HSC 谱系发育以抑制远端脑炎症，提示骨髓是自我保护神经免疫相互作用的独特龛位，这可能被利用来获得治疗效果。
