Immune Pathway Activation in Neurons Triggers Neural Damage after Stroke.

Ischemic brain injury is a severe medical condition with high incidences in elderly people without effective treatment for the resulting neural damages. Using a unilateral mouse stroke model, we analyze single-cell transcriptomes of ipsilateral and contralateral cortical penumbra regions to objectively reveal molecular events with single-cell resolution at 4 h and 1, 3, and 7 days post-injury. Here, we report that neurons are among the first cells that sense the lack of blood supplies by elevated expression of CCAAT/enhancer-bind-ing protein 0 (C/EBP0). To our surprise, the canonical inflammatory cytokine gene targets for C/EBP0, including interleukin-10 (IL-10) and tumor necrosis factor a (TNF-a), are subsequently induced also in neuronal cells. Neuronal-specific silencing of C/EBP0 or IL-10 and TNF-a substantially alleviates down-stream inflammatory injury responses and is profoundly neural protective. Taken together, our findings reveal a neuronal inflammatory mechanism underlying early pathological triggers of ischemic brain injury.