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

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. 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. 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. 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.

• Publication year

  2019

• Venue

  Journal of Neuroinflammation

• Publication date

  2019-08-31

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/s12974-019-1557-6PMID 31472680PMCID 6717357
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• STAT1 signaling mediated the regulation of neutrophil functions by all-trans retinoic acid, and neutrophil depletion showed those functions were required for protection.

  Confidence 0.91

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) reviewq (76h6bfydm6) reviewAK (4715169a40) reviewAnonymous (12632b8b5f) reviewjihoonc (k5vuy3tzcm) review
• All-trans retinoic acid shifted neutrophils toward an N2 phenotype and inhibited neutrophil extracellular trap formation.

  Confidence 0.94

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) reviewq (76h6bfydm6) reviewAK (4715169a40) reviewAnonymous (12632b8b5f) reviewjihoonc (k5vuy3tzcm) review
• All-trans retinoic acid attenuated neural inflammation and decreased neutrophil accumulation in the stroke lesion.

  Confidence 0.95

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• All-trans retinoic acid reduced infarct volume and neurological deficits 1 day after transient middle cerebral artery occlusion in mice.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) reviewq (76h6bfydm6) reviewAK (4715169a40) reviewAnonymous (12632b8b5f) reviewjihoonc (k5vuy3tzcm) review

• acute ischemic stroke

  condition

  A stroke caused by interrupted cerebral blood flow, represented here as the disease context for the mouse model.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) reviewq (76h6bfydm6) reviewAK (4715169a40) reviewAnonymous (12632b8b5f) reviewjihoonc (k5vuy3tzcm) review
• all-trans retinoic acid

  treatment, compound

  A retinoid compound used here as the experimental treatment in mice and primary neutrophil cultures.

  Aliases: atRA, all trans-retinoic acid

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• n2 phenotype

  cell phenotype

  An anti-inflammatory neutrophil polarization state described in the lesion and in culture.

  Aliases: N2 neutrophils

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• neural inflammation

  biological process

  Inflammatory activity in neural tissue after ischemic injury.

  박진우 (dztg5apj7m) extractionB (s683577b42) review--------- ✂ Cut Here ✂ --------- (jqthcshryb) reviewq (76h6bfydm6) reviewAK (4715169a40) reviewAnonymous (12632b8b5f) reviewjihoonc (k5vuy3tzcm) review
• neutrophil depletion

  experimental intervention

  Experimental removal of neutrophils using anti-Ly6G antibodies.

  Aliases: anti-Ly6G depletion, Ly6G depletion

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• neutrophil extracellular traps

  immune structure, cellular product

  Web-like chromatin-protein structures released by activated neutrophils.

  Aliases: NETs

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• neutrophil functions

  cellular process

  Functional behaviors of neutrophils relevant to lesion inflammation, including polarization, clearance, and extracellular trap release.

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• stat1 signaling

  signaling pathway

  A STAT1-dependent signaling pathway involved in immune regulation.

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• transient middle cerebral artery occlusion

  animal model, procedure

  A mouse surgery that transiently blocks the middle cerebral artery to induce focal cerebral ischemia.

  Aliases: tMCAO

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