Interleukin 13 promotes long-term recovery after ischemic stroke by inhibiting the activation of STAT3

Abstract Background Microglia/macrophages are activated after cerebral ischemic stroke and can contribute to either brain injury or recovery by polarizing microglia/macrophage into distinctive functional phenotypes with pro- or anti-inflammatory properties. Interleukin-13 (IL-13) is an anti-inflammatory cytokine that regulates microglia/macrophage polarization toward an anti-inflammatory phenotype. However, it is not clear whether IL-13 is beneficial after ischemic stroke long-term and the underlying molecular mechanism(s) remain unknown. Thus, we examined the effect of IL-13 on long-term recovery and microglia/macrophage polarization in mice with transient middle cerebral artery occlusion model (tMCAO). Methods tMCAO was induced in adult male C57BL/6J mice. IL-13 (60 μg/kg) was administered intranasally starting 2 h after stroke and continued for seven consecutive days. Sensorimotor function, spatial learning and memory function, as well as brain infarct volume were assessed up to 35 days after stroke. White matter integrity was evaluated by electrophysiology, immunofluorescence staining, and transmission electron microscopy. Microglia/macrophage activation was assessed using immunofluorescence staining and quantitative real-time polymerase chain reaction. Changes in immune cells in the brain and the periphery, and expression of IL-13 receptors in different brain cells were detected by flow cytometry. Primary neuron/microglia co-cultures and a STAT3 inhibitor were used for mechanistic studies. Results Post-treatment with IL-13 improved long-term neurofunctional recovery and decreased brain tissue atrophy after stroke. Intranasal delivery of IL-13 enhanced the structural and functional integrity of white matter after stroke. Furthermore, the neuroprotection afforded by IL-13 administration was not due to a direct effect on neurons, but by indirectly regulating the anti-inflammatory phenotype of microglia/macrophages. IL-13 treatment also had no effect on peripheral immune cells. Mechanistically, IL-13 improved the long-term outcome after ischemic stroke by promoting the polarization of microglia/macrophages toward the anti-inflammatory phenotype at least partially by inhibiting the phosphorylation of STAT3. Conclusions IL-13 promotes white matter repair and improves neurofunctional outcomes after ischemic stroke by modulating microglia/macrophages via inhibition of STAT3 phosphorylation.