Brain Ischemia Suppresses Immunity in the Periphery and Brain via Different Neurogenic Innervations

• Published in: Immunity (Cambridge, Mass.) Mass.), 2017-03, Vol.46 (3), p.474-487
• Main Authors: Liu, Qiang, Jin, Wei-Na, Liu, Yaou, Shi, Kaibin, Sun, Haoran, Zhang, Fang, Zhang, Chao, Gonzales, Rayna J., Sheth, Kevin N., La Cava, Antonio, Shi, Fu-Dong
• Format: Article
• Language: English
• Subjects: Ablation; Aged; Animals; Antibiotics; Atrophy; Brain; Brain - immunology; brain ischemia; Brain Ischemia - complications; Brain Ischemia - immunology; Cerebral ischemic disease; Compartments; Complications; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Gene Expression Profiling; Humans; Immune response; Immune system; Immunity; Infection - etiology; Infection - immunology; Infections; Ischemia; Killer Cells, Natural - immunology; Male; Mice; Mice, Inbred C57BL; natural killer (NK) cells; Nervous system; neurogenic innervation; NMR; Nuclear magnetic resonance; Occlusion; Pharmacology; post-stroke infection; Real-Time Polymerase Chain Reaction; Rodents; Spleen; Spleen - immunology; Stroke; T cell receptors; Transcriptome
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2017.02.015

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 restrained 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. •Brain ischemia causes transient but severe suppression of cellular immunity•Natural killer (NK) cells display different profiles in the CNS versus periphery after stroke•NK cell response is shaped by organ-specific neurogenic innervation after stroke•Modulation of neurogenic innervation limits post-stroke infection Liu and colleagues demonstrate that brain ischemia shapes innate cellular immune responses in the periphery and the brain through different neurogenic and intracellular pathways. Targeted modulation of neurogenic innervation is capable of inhibiting post-stroke infection.