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 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.
Departments of Neurology and Radiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. Electronic address: qliu.asu@gmail.com.
Qiang
Q
Liu
Departments of Neurology and Radiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Wei-Na
WN
Jin
Departments of Neurology and Radiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Yaou
Y
Liu
Departments of Neurology and Radiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Kaibin
K
Shi
Departments of Neurology and Radiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Haoran
H
Sun
Departments of Neurology and Radiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Fang
F
Zhang
Departments of Neurology and Radiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Chao
C
Zhang
Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, USA.
Rayna J
RJ
Gonzales
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.
Kevin N
KN
Sheth
Department of Medicine, University of California, Los Angeles, CA 90095, USA.
Antonio
A
La Cava
Departments of Neurology and Radiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA. Electronic address: fshi@tmu.edu.cn.
Fu-Dong
FD
Shi
D000368:Aged; D000818:Animals; D001921:Brain / Q000276:immunology*; D002545:Brain Ischemia / Q000150:complications / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007239:Infections / Q000209:etiology / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology*; D059467:Transcriptome
brain ischemia; immunity; natural killer (NK) cells; neurogenic innervation; post-stroke infection