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

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 <i>Il-4</i> gene aggravates I/R injury <i>in vivo</i> and exacerbates oxygen-glucose deprivation (OGD) injury in cortical neurons. Conversely, supplemental IL-4 protects <i>Il-4</i> ^-/- 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 <i>Il-4</i> ^-/- mice. Furthermore, upregulation of Nav1.1 channel, and downregulations of KCa3.1 channel and <i>α</i>6 subunit of GABA_A receptors are detected in the cortical tissues and primary cortical neurons from <i>Il-4</i> ^-/- 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.