All trans-retinoic acid protects against acute ischemic stroke by modulating neutrophil functions through STAT1 signaling. J Neuroinflammation 2019 Aug 31;16(1):175
Date
09/02/2019Pubmed ID
31472680Pubmed Central ID
PMC6717357DOI
10.1186/s12974-019-1557-6Scopus ID
2-s2.0-85071686674 (requires institutional sign-in at Scopus site) 63 CitationsAbstract
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.
Author List
Cai W, Wang J, Hu M, Chen X, Lu Z, Bellanti JA, Zheng SGAuthor
Xiao Chen MD, PhD Associate Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBrain Ischemia
Cells, Cultured
Female
Male
Mice
Mice, Inbred C57BL
Neuroprotective Agents
Neutrophils
STAT1 Transcription Factor
Signal Transduction
Stroke
Tretinoin
