Wattananit Somsak, Tornero Daniel, Graubardt Nadine, Memanishvili Tamar, Monni Emanuela, Tatarishvili Jemal, Miskinyte Giedre, Ge Ruimin, Ahlenius Henrik, Lindvall Olle, Schwartz Michal, Kokaia Zaal
Laboratory of Stem Cells and Restorative Neurology and.
Department of Neurobiology, Weizmann Institute of Science, 7610001, Rehovot, Israel, and.
J Neurosci. 2016 Apr 13;36(15):4182-95. doi: 10.1523/JNEUROSCI.4317-15.2016.
Stroke is a leading cause of disability and currently lacks effective therapy enabling long-term functional recovery. Ischemic brain injury causes local inflammation, which involves both activated resident microglia and infiltrating immune cells, including monocytes. Monocyte-derived macrophages (MDMs) exhibit a high degree of functional plasticity. Here, we determined the role of MDMs in long-term spontaneous functional recovery after middle cerebral artery occlusion in mice. Analyses by flow cytometry and immunocytochemistry revealed that monocytes home to the stroke-injured hemisphere., and that infiltration peaks 3 d after stroke. At day 7, half of the infiltrating MDMs exhibited a bias toward a proinflammatory phenotype and the other half toward an anti-inflammatory phenotype, but during the subsequent 2 weeks, MDMs with an anti-inflammatory phenotype dominated. Blocking monocyte recruitment using the anti-CCR2 antibody MC-21 during the first week after stroke abolished long-term behavioral recovery, as determined in corridor and staircase tests, and drastically decreased tissue expression of anti-inflammatory genes, including TGFβ, CD163, and Ym1. Our results show that spontaneously recruited monocytes to the injured brain early after the insult contribute to long-term functional recovery after stroke.
For decades, any involvement of circulating immune cells in CNS repair was completely denied. Only over the past few years has involvement of monocyte-derived macrophages (MDMs) in CNS repair received appreciation. We show here, for the first time, that MDMs recruited to the injured brain early after ischemic stroke contribute to long-term spontaneous functional recovery through inflammation-resolving activity. Our data raise the possibility that inadequate recruitment of MDMs to the brain after stroke underlies the incomplete functional recovery seen in patients and that boosting homing of MDMs with an anti-inflammatory bias to the injured brain tissue may be a new therapeutic approach to promote long-term improvement after stroke.
中风是导致残疾的主要原因，目前缺乏能实现长期功能恢复的有效治疗方法。缺血性脑损伤会引发局部炎症，这涉及活化的常驻小胶质细胞和浸润的免疫细胞，包括单核细胞。单核细胞衍生的巨噬细胞（MDM）表现出高度的功能可塑性。在此，我们确定了MDM在小鼠大脑中动脉闭塞后长期自发功能恢复中的作用。通过流式细胞术和免疫细胞化学分析发现，单核细胞归巢至中风损伤的半球，且浸润在中风后3天达到峰值。在第7天，一半浸润的MDM表现出促炎表型倾向，另一半表现出抗炎表型倾向，但在随后的2周内，具有抗炎表型的MDM占主导。在中风后的第一周使用抗CCR2抗体MC - 21阻断单核细胞募集，如在走廊和楼梯测试中所确定的，消除了长期行为恢复，并大幅降低了包括TGFβ、CD163和Ym1在内的抗炎基因的组织表达。我们的结果表明，在损伤后早期自发募集到受损大脑的单核细胞有助于中风后的长期功能恢复。
几十年来，循环免疫细胞在中枢神经系统修复中的任何作用都被完全否定。直到过去几年，单核细胞衍生的巨噬细胞（MDM）在中枢神经系统修复中的作用才得到认可。我们在此首次表明，缺血性中风后早期募集到受损大脑的MDM通过炎症消退活动促进长期自发功能恢复。我们的数据提出了一种可能性，即中风后MDM向大脑的募集不足是患者功能恢复不完全的原因，并且增强具有抗炎倾向的MDM向受损脑组织的归巢可能是促进中风后长期改善的一种新的治疗方法。
