Monocyte-Derived Macrophages Contribute to Spontaneous Long-Term Functional Recovery after Stroke in Mice

作者：Somsak Wattananit, Daniel Tornero, Nadine Graubardt, Tamar Memanishvili, Emanuela Monni, Jemal Tatarishvili, Giedre Miskinyte, Ruimin Ge, Henrik Ahlenius, Olle Lindvall, Michal Schwartz, Zaal Kokaia · 发表于：Journal of Neuroscience · 年份：2016 · DOI：10.1523/jneurosci.4317-15.2016 · 被引用次数：362 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Stroke Rehabilitation and Recovery、Intracerebral and Subarachnoid Hemorrhage Research

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. SIGNIFICANCE STATEMENT: For decades, any involvement of circulating immune cells in CNS repair was completely denied. Only over the past few years has involvement of mono...