All trans-retinoic acid protects against acute ischemic stroke by modulating neutrophil functions through STAT1 signaling

Abstract

Background and purpose Regulation of neural inflammation is considered as a vital therapeutic target in ischemic stroke. All-trans retinoic acid (atRA), a potent immune modulator, has raised interest in the field of stroke therapy. However, the immunological mechanisms for atRA-mediated neuroprotection remain elusive. The current study evaluated the impact of atRA on post-stroke neural inflammation and elucidated the mechanisms involved in the regulation of related neutrophil functions. Methods atRA was prophylactically administered to mice 1 day before transient middle cerebral artery occlusion (tMCAO, 1 h) and repeated daily immediately after reperfusion for 3 days. Stroke outcomes, neutrophil polarization, and formation of neutrophil extracellular traps (NETs) in the stroke lesion were assessed. Neutrophil depletion was induced with anti-Ly6G antibodies. Primary neutrophil cultures were used to explore the mechanisms of atRA treatment. Results Prophylactic atRA treatment reduced infarct volumes and neurological deficits at 1 day after tMCAO. Post-stroke neural inflammation was attenuated and neutrophil accumulation in lesion was downregulated. atRA treatment skewed neutrophil toward N2 phenotype which facilitated its clearance by macrophage and inhibited NETs formation. The functions of neutrophil were indispensable in the protective effects of atRA and were associated with suppression to STAT1 signaling by atRA. Administration of atRA after stroke still provided efficient protection to cerebral ischemia. Conclusion atRA displays potent therapeutic efficacy in ischemic stroke by attenuating neural inflammation. Treatment of atRA impeded neutrophil accumulation, favored N2 polarization, and forbade NETs formation in ischemic lesion. STAT1 signaling played a decisive role in the mechanisms of atRA-afforded regulation to neutrophil. Electronic supplementary material The online version of this article (10.1186/s12974-019-1557-6) contains supplementary material, which is available to authorized users.

Administration of all‐transretinoic acid after experimental traumatic brain injury is brain protective

“…Administration of ATRA also exerted neuroprotective actions in animal models of focal or global brain ischaemia (Cai et al, 2019; Kim et al, 2013; Kong et al, 2015; Li et al, 2018; Yu et al, 2017). Similar to our findings, the authors observed reduced infarction volume.…”

Post-Treatment of Synthetic Polyphenolic 1,3,4 Oxadiazole Compound A3, Attenuated Ischemic Stroke-Induced Neuroinflammation and Neurodegeneration

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Cordycepin Confers long-term neuroprotection via inhibiting neutrophil infiltration and neuroinflammation after traumatic brain injury

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