Abstract
Natural killer (NK) cells, a key member of innate lymphocytes, are a promising immunotherapeutic target for ischemic stroke. Astragaloside IV (ASIV) is isolated from Astragalus mongholicus Bunge (Fabaceae), a herbal medicine possessing immunomodulatory ability. This study investigated the effect of ASIV on NK cells during the acute stage of brain ischemic injury in a mouse model of middle cerebral artery occlusion (MCAO). MCAO mice treated with ASIV had better functional outcomes, smaller brain infarction and less NK cell brain infiltration. NK cell depletion echoed the protective effect of ASIV. Notably, ASIV did not enhance the protective effect of NK cell depletion against brain ischemic injury. ASIV inhibited glial cell-derived CCL2-mediated chemotaxis to prevent post-ischemic NK cell brain recruitment. Meanwhile, ASIV also abrogated NK cell-mediated cytolytic killing of neurons subjected to oxygen-glucose deprivation and suppressed NK cell-derived IFN-γ and NKG2D expression in the ischemic brain. The inhibitory effect of ASIV on NK cell brain infiltration and activation was mimicked by cryptotanshinone, a STAT3 inhibitor. There was no additive effect when ASIV and cryptotanshinone were used together. In conclusion, ASIV inhibits post-ischemic brain infiltration and activation of NK cells through STAT3 suppression, and this inhibitory effect of ASIV on NK cells plays a key role in its protection against acute ischemic brain injury. Our findings suggest that ASIV is a promising therapeutic candidate in NK cell-based immunotherapy for the treatment of acute ischemic stroke and pave the way for potential clinical trials.
Highlights
Ischemic stroke accounts for approximately 80% of all strokes and is associated with high morbidity and mortality worldwide
We found that Astragaloside IV (ASIV) can suppress post-ischemic infiltration and activation of Natural killer (NK) cells in the ischemic brain of middle cerebral artery occlusion (MCAO) mice, which may eventually contribute to the beneficial effects of ASIV against acute brain ischemic injury
We evaluated the protective effects of ASIV at 20 and 40 mg/kg in MCAO mice on Day 1 after reperfusion
Summary
Ischemic stroke accounts for approximately 80% of all strokes and is associated with high morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only FDAapproved intervention for ischemic stroke. Only a minority of stroke patients is eligible for rtPA treatment due to its narrow therapeutic time window and the potential risk of intracranial hemorrhage (Fonarow et al, 2011). It is urgent to develop new treatments for ischemic stroke. Immune responses closely participate in all stages of ischemic cascade, from acute injury to long-term recovery, and shape the outcome of stroke ASIV Suppresses NK Cells et al, 2020). Upon the occurrence of brain ischemia, breached blood-brain barrier (BBB) allows infiltration of large amount of peripheral immune cells to the brain parenchyma (Planas, 2018). Natural killer (NK) cells are one of the first responders
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