Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti‐inflammatory phenotype through STAT3 pathway

CNS Neuroscience and Therapeutics - Tập 25 Số 12 - Trang 1353-1362 - 2019
Zongjian Liu1, Yuanyuan Ran1, Shuyan Qie1, Weijun Gong1, Fuhai Gao1, Zitong Ding1, Jianing Xi1
1Department of Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China

Tóm tắt

AbstractAimsMicroglia and infiltrated macrophages play important roles in inflammatory processes after ischemic stroke. Modulating microglia/macrophage polarization from pro‐inflammatory phenotype to anti‐inflammatory state has been suggested as a potential therapeutic approach in the treatment of ischemic stroke. Melatonin has been shown to be neuroprotective in experimental stroke models. However, the effect of melatonin on microglia polarization after stroke and underlying mechanisms remain unknown.MethodsIn vivo, cerebral ischemia was induced by distal middle cerebral artery occlusion (dMCAO) in C57BL/6J mice. Melatonin was injected intraperitoneally (20 mg/kg) at 0 and 24 hours after ischemia. In vitro, the microglial cell line BV2 was stimulated to the pro‐inflammatory state with conditioned media (CM) collected from oxygen‐glucose deprivation (OGD) challenged neuronal cell line Neuro‐2a (N2a). Real‐time PCR was utilized to detect the mRNA expression of microglia phenotype markers. Activation of signal transducer and activator of transcription 3 (STAT3) pathway was determined by Western blot of phosphorylated STAT3 (pSTAT3). A neuron‐microglia co‐culture system was used to determine whether melatonin can inhibit the neurotoxic effect of pro‐inflammatory microglia to post‐OGD neurons.ResultsMelatonin treatment reduced brain infarct and improved neurological functions 3 days after dMCAO, which was accompanied by decreased expression of pro‐inflammatory markers and increased expression of anti‐inflammatory markers in the ischemic brain. In vitro studies confirmed that melatonin directly inhibited the pro‐inflammatory responses in BV2 cells upon exposure to OGD neuron CM. The microglia possessing pro‐inflammatory phenotype exacerbated post‐OGD N2a cells death, whereas melatonin reduced such neurotoxic effect. Further, melatonin enhanced the otherwise inhibited pSTAT3 expression in BV2 cells treated with OGD neuron CM. STAT3 blockade significantly reduced the effect of melatonin on microglial phenotype shift. Conclusion: Melatonin treatment ameliorates brain damage at least partially through shifting microglia phenotype from pro‐inflammatory to anti‐inflammatory polarity in a STAT3‐dependent manner.

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Tài liệu tham khảo

10.1159/000356320

10.1111/j.1600-079X.2004.00173.x

10.3389/fimmu.2019.01668

10.1016/j.pneurobio.2013.12.002

10.1002/glia.22298

10.1161/STROKEAHA.117.018505

10.1161/STROKEAHA.112.659656

10.4049/jimmunol.172.1.567

10.1177/0271678X17694185

10.1111/cns.12577

10.1186/s12974-015-0270-3

10.1177/0271678X16679671

10.1016/j.biopha.2019.109102

10.1038/s41598-019-48759-0

10.3389/fnagi.2017.00233

10.1186/s12974-016-0541-7

10.1177/0271678X17713105

10.1177/0271678X16680003

10.1177/0271678X18808174

10.1111/cns.13061

10.1177/1179069519827300

10.1002/jnr.24220

10.1016/j.pharmthera.2015.06.010

10.1097/00004647-199905000-00005

10.1038/sj.jcbfm.9600603

10.1016/j.lfs.2014.01.085

10.4103/1673-5374.228711

10.1016/j.brainres.2019.146401

10.14336/AD.2016.0320

10.1186/s12974-017-0843-4

10.1016/j.intimp.2014.12.035

10.20945/2359-3997000000066

10.1177/0300060518775008

10.1111/jpi.12114

10.3727/096368915X689749

10.3390/molecules23020301

Lin YU, 2018, Melatonin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress, Int J Mol Med, 42, 182

10.1007/s12026-009-8150-5

10.1038/jcbfm.2013.155

10.1161/STROKEAHA.110.593772

10.1177/0271678X16648712

10.1016/j.expneurol.2015.03.021

10.1038/nrneurol.2014.207

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CNS Neuroscience and Therapeutics

Tập 25 Số 12

1353-1362

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