Deficiency of anti-inflammatory cytokine IL-4 leads to neural hyperexcitability and aggravates cerebral ischemia-reperfusion injury

Xiaoling Chen; Jingliang Zhang; Yan Song; Pan Yang; Yang Yang; Zhuo Huang; Kewei Wang

doi:10.1016/j.apsb.2020.05.002

Deficiency of anti-inflammatory cytokine IL-4 leads to neural hyperexcitability and aggravates cerebral ischemia-reperfusion injury

Acta Pharm Sin B. 2020 Sep;10(9):1634-1645. doi: 10.1016/j.apsb.2020.05.002. Epub 2020 May 20.

Authors

Xiaoling Chen¹, Jingliang Zhang¹, Yan Song¹, Pan Yang², Yang Yang³, Zhuo Huang¹, Kewei Wang^{1

2

4}

Affiliations

¹ Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, Beijing 100191, China.
² Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao 266021, China.
³ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, West Lafayette, IN 47907, USA.
⁴ Institute of Innovative Drugs, Qingdao University School of Pharmacy, Qingdao 266021, China.

Abstract

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 GABA_A 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.

Keywords: Anoxic depolarization; IL-4; Ischemia–reperfusion injury; Neuronal excitability; Synaptic transmissions.