Social isolation initiated post-weaning augments ischemic brain injury by promoting pro-inflammatory responses

Social isolation is associated with poor stroke outcome, but the underlying molecular mechanisms were largely unknown. In male Balb/C mice exposed to transient middle cerebral artery occlusion (MCAo), we examined the effects of social isolation initiated post-weaning on ischemic injury, cytokine/chemokine responses and cell signaling using a broad panel of techniques that involved immunocytochemistry, cytokine/chemokine array and Western blots. Social isolation initiated post-weaning elevated infarct size, brain edema and neuronal injury in the ischemic brain tissue 3 days after MCAo, and increased microglia/ macrophage and leukocyte accumulation. In line with the increased immune cell recruitment, levels of several proinflammatory cytokines (e.g., IL-1α, IL-1β, IL-13, IL-17, TNF-α, IFN-γ), chemokines (e.g., CCL3, CCL4, CCL12, CXCL2, CXCL9, CXCL12) and adhesion molecules (i.e., ICAM-1) were increased in the ischemic brain tissue of socially isolated compared with paired housing mice, whereas levels of selected cytokines (IL-5, IL-6, IL-16) and colony-stimulating factors (G-CSF, GM-CSF) were reduced. The activity of the transcription factor nuclear factor-ĸB (NF-ĸB), which promotes cell injury via pro-inflammatory responses, was increased by social isolation, whereas that of nuclear factor erythroid related factor-2 (Nrf-2), which mediates anti-oxidative responses under oxidative stress conditions, was reduced. Our study shows that social isolation profoundly alters post-ischemic cell signaling in a way promoting pro-inflammatory responses. Our results highlight the importance of social support in preventing deleterious health effects of social isolation. [Display omitted] •Post-weaning social isolation augments ischemic brain injury and edema post-MCAo.•Social isolation enhances microglia and leukocyte accumulation in ischemic brain.•Social isolation lowers astrocyte GFAP immunoreactivity in ischemic striatum.•Isolated mice show higher specific pro-inflammatory cytokine response to stroke.•Social isolation activates NF-κB and reduces Nrf-2 in ischemic striatum.