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

Abstract

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 longterm 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 TGF␤, 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.

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Some of the most intriguing data that have emerged from the field of neuroimmunology indicate that in the context of CNS injury, T effector cells and even monocytes can traffic to the brain and induce repair processes that have a significant impact on the extent of tissue damage and destruction (Schwartz and Shechter, 2010;Wattananit et al, 2016). For example, after partial crush injury of the optic nerve, T cells immunized to specific CNS antigens (ie, myelin basic protein) were found to protect against secondary nerve degeneration (Moalem et al, 1999).…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…A recent study also supports the view of macrophage conversion at the injury site. Wattananit et al [117] showed a beneficial role for early recruited CCR2 + monocyte-derived macrophages on functional recovery through enhancing resolution of inflammation. While there have been advances in understanding the role of mononuclear phagocytes in stroke, defining the phenotype of mononuclear phagocytes relevant to their function in the poststroke brain has been understudied.…”

Immunopathogenetic Aspects of Ischemic Stroke

“…Аналогичные данные получены Gliem M. и соавт., которые продемонстрировали, что провоспалительные моноциты быстро рекру-тируются в зону ишемии через CCR2-зависимый путь и дифференцируются в макрофаги, обеспе-чивающие нейропротекцию и нейроваскулярную репарацию в зоне ишемии [37]. Стимулирующий эффект рекрутируемых макрофагов на невроло-гическое восстановление в отдаленном перио-де инсульта продемонстрирован недавно [129]. Авторы показали, что на 7 сутки после инсульта половина рекрутируемых макрофагов экспрес-сирует М2-, а половина -М1-фенотип.…”