Abstract

Background: Immune responses after stroke, including both in situ glial cell activation and peripheral immune cell infiltration, play critical roles in ischemic brain injury. Systemic docosahexaenoic acid (DHA) has been explored as a clinically feasible protectant in stroke models. However, the mechanism for DHA-afforded neuroprotection remains elusive. This study evaluated the effect of systemic DHA treatment after transient cerebral ischemia and elucidated a mechanism involving immune regulation of macrophages. Methods: Transient middle cerebral artery occlusion (tMCAO) was induced for 1 hour. DHA (i.p., 10mg/kg) was administered immediately after reperfusion and repeated daily for 3 days. Stroke outcomes, systemic inflammatory status and microglia/macrophage phenotypic alterations were assessed 3 days after stroke. Macrophage depletions were induced by clodronate liposomes injection. Primary macrophage cultures were used to evaluate the direct effect of DHA on macrophages. Results: Post-stroke DHA injection efficiently reduced brain infarct and ameliorated neurological deficits 3 days after tMCAO. Systemic DHA treatment significantly inhibited immune cell infiltration (macrophages, neutrophils, T lymphocytes and B lymphocytes) and promoted macrophage polarization towards an anti-inflammatory M2 phenotype in the ischemic brain. Meanwhile, systemic DHA administration inhibited the otherwise elevated pro-inflammatory factors in blood and shifted circulating macrophage polarity toward M2 phenotype after ischemic stroke. The numbers of circulating immune cells in blood and spleen, however, were equivalent between DHA and vehicle treated groups. The protective effects of DHA were macrophage-dependent, as macrophage depletion abolished DHA-afforded neuroprotection. In vitro studies confirmed that DHA suppressed production of chemokines and pro-inflammatory cytokines from macrophages under inflammatory stimulation. Conclusion: Post-stroke DHA treatment ameliorated acute ischemic brain injury in a macrophage-dependent manner. DHA enhanced macrophage phenotypic shift toward an anti-inflammatory phenotype and therefore reduced central and peripheral inflammation after stroke.

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