Brain ischemia suppresses immunity in the periphery and brain via different neurogenic innervations

Brain ischemia inhibits immune function systemically, with resulting infectious complications. Whether in stroke different immune alterations occur in brain and periphery and whether analogous mechanisms operate in these compartments remains unclear. Here we show that in patients with ischemic stroke and in mice subjected to middle cerebral artery occlusion, natural killer (NK) cells display remarkably distinct temporal and transcriptome profiles in the brain as compared to the periphery. The activation of catecholaminergic and hypothalamic-pituitary-adrenal axis leads to splenic atrophy and contraction of NK cell numbers in the periphery through a modulated expression of SOCS3, whereas cholinergic innervation-mediated suppression of NK cell responses in the brain involves RUNX3. Importantly, pharmacological or genetic ablation of innervation preserved NK cell function and prevented post-stroke infection. Thus, brain ischemia compromises NK cell-mediated immune defenses through mechanisms that differ in the brain versus the periphery, and targeted inhibition of neurogenic innervation limits post-stroke infection. NK cells were isolated from pooled splenocytes and brain tissues of B6 mice at days 1 or 3 after MCAO (n=3 at each time point) or sham-operations(n=3). RNA of FACS-sorted brain-infiltrating NK cells was obtained from pooled brain tissues of MCAO mice. RNA of FACS-sorted NK cells in spleens was obtained from single mouse spleens of MCAO mice. RNA samples for each data point were harvested from four individual experiments. The purity of FACS-sorted NK cells was >99%. RNA was purified using TRIzol reagent (Ambion, Grand Island, NY, USA) according to the manufacturer’s protocol. RNA samples were analyzed by nCounter gene expression analysis and quantified using nCounter Digital Analyzer (NanoString Technologies, Tucson, AZ, USA).