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Deficiency of anti-inflammatory cytokine IL-4 leads to neural hyperexcitability and aggravates cerebral ischemia–reperfusion injury
Acta Pharmaceutica Sinica B ( IF 14.5 ) Pub Date : 2020-05-20 , DOI: 10.1016/j.apsb.2020.05.002
Xiaoling Chen , Jingliang Zhang , Yan Song , Pan Yang , Yang Yang , Zhuo Huang , Kewei Wang

Systematic administration of anti-inflammatory cytokine interleukin 4 (IL-4) has been shown to improve recovery after cerebral ischemic stroke. However, whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown. Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia–reperfusion (I/R) injury. In multi-electrode array (MEA) recordings, IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons. IL-4 mRNA and protein expressions are upregulated after I/R injury. Genetic deletion of Il-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation (OGD) injury in cortical neurons. Conversely, supplemental IL-4 protects Il-4−/− cortical neurons against OGD injury. Mechanistically, cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4−/− mice. Furthermore, upregulation of Nav1.1 channel, and downregulations of KCa3.1 channel and α6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4−/− mice. Taken together, our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury, thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.



中文翻译:

抗炎细胞因子IL-4缺乏会导致神经过度兴奋并加重脑缺血再灌注损伤

研究表明,抗炎细胞因子白介素4(IL-4)的系统给药可改善脑缺血性中风后的恢复。但是,IL-4是否会影响神经元兴奋性以及IL-4如何改善缺血性损伤尚不清楚。在这里,我们报道内源性IL-4在局灶性脑缺血再灌注(I / R)损伤中的神经保护作用。在多电极阵列(MEA)记录中,IL-4减少了小鼠原代皮层神经元的自发放电和网络活动。I / R损伤后IL-4 mRNA和蛋白表达上调。Il-4基因的遗传删除在体内加重了I / R损伤并加剧了皮层神经元的氧葡萄糖剥夺(OGD)损伤。相反,补充IL-4可保护Il-4 -/-皮质神经元抵抗OGD损伤。机械上,I / R损伤后缺血半影常见的皮质锥体和星状神经元在Il-4 -/-小鼠中表现出内在的过度兴奋性和兴奋性突触传递。此外,Nav1.1通道,和KCa3.1通道和downregulations上调α GABA的6亚基皮质组织和初级皮层神经元中检测到从受体IL-4 - / -老鼠。综上,我们的发现表明IL-4缺乏会导致神经过度兴奋并加重I / R损伤,因此IL-4信号的激活可能保护大脑免受永久性损伤的发展,并有助于中风后缺血性损伤的恢复。

更新日期:2020-05-20
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