Central nervous system (CNS)-infiltrating lymphocytes contribute to the progression of cerebral infarction in ischemic stroke. The damaged brain, in turn, exerts suppressive effects on the immune system. The temporal relationship of this reciprocal interaction between immune system and ischemic brain has not been defined, making immune intervention to limit brain damage exceedingly difficult. Moreover, the high prevalence of infection in stroke patients requires a better understanding of how stroke influences immune responses systemically and within the brain, to combat immune-related post-stroke complications. We recently showed that natural killer (NK) cells - a critical component of the innate immune system - are abundantly represented in peri-infarcted area of brain sections from autopsies of stroke patients. In a mouse model of cerebral ischemia, we showed that ischemic neuron-derived fractalkine recruited NK cells, which could accelerate brain infarction in the acute stage of ischemic stroke. Subsequently, NK cells exhibited decreased frequency and compromised function. Those NK cells expressed neurotransmitter receptors, and their exposure to acetylcholine impaired function. Based on these findings, we hypothesize that the physical proximity of ischemic neurons and NK cells in the CNS, as well as different neuronal signals received by NK cells within the CNS and the peripheral lymphoid organs, underlie the differential mechanisms responsible for NK cell deficiency in the periphery and in the brain. This would lead to NK cell-associated immune deficiency that favors the development of infection and post-stroke complications. To test this hypothesis, we will analyze the pathways that lead to NK cell deficiency in stroke, and relate those findings to clinical outcomes.
The specific aims are: 1) To define the temporal events associated with functional changes in NK cells from competency to deficiency, and to identify the characteristics acquired by NK cells in the periphery and in the CNS after brain ischemia; 2) To identify the mechanisms responsible for NK cell deficiency in the periphery and in the CNS after brain ischemia; 3) To investigate the clinical relevance of NK cell deficiency on infection in stroke, and to test strategies of manipulation of NK cell deficiency for the reduction of post-stroke infection. In all, this proposa will advance the understanding of key neuroimmune interactions that might allow design of strategies of NK cell-based intervention as a new tool limiting risks of post-stroke infection.

Public Health Relevance

are major complications in stroke patients, and often lead to sustained disability and/or elevated mortality rate in those patients. The inhibition of immunity after brain cessation of blood supply has been recongnized as a central cause of infection in stroke patients. However, since the mechanisms involved in the process are not known, attempts to reverse stroke-associated immune deficiency is both problematic and non- specific. Natural killer (NK) cells are immune cells that are recruited as first barrier to fight pathogens, and orchestrate protective activities at the level of both the innate and adaptive immune systems. During ischemic stroke, NK cells become significantly impaired and reduced in number. In this project, we will dissect how ischemic brain injury leads to NK cell deficiency, to better understand the interplay between the immune and nervous systems after brain ischemia. Importantly, we will also test new strategies to manipulate NK cells as a new approach to improve host immune defenses in post-stroke patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092713-02
Application #
9249129
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Bosetti, Francesca
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
St. Joseph's Hospital and Medical Center
Department
Type
DUNS #
131606022
City
Phoenix
State
AZ
Country
United States
Zip Code
85013
Liu, Qiang; Jin, Wei-Na; Liu, Yaou et al. (2017) Brain Ischemia Suppresses Immunity in the Periphery and Brain via Different Neurogenic Innervations. Immunity 46:474-487
Li, Zhiguo; Li, Minshu; Wood, Kristofer et al. (2017) Engineered agrin attenuates the severity of experimental autoimmune myasthenia gravis. Muscle Nerve :
Li, Minshu; Ren, Honglei; Sheth, Kevin N et al. (2017) A TSPO ligand attenuates brain injury after intracerebral hemorrhage. FASEB J 31:3278-3287
Li, Minshu; Li, Zhiguo; Yao, Yang et al. (2017) Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity. Proc Natl Acad Sci U S A 114:E396-E405
Feng, Yan; Liao, Shiwei; Wei, Changjuan et al. (2017) Infiltration and persistence of lymphocytes during late-stage cerebral ischemia in middle cerebral artery occlusion and photothrombotic stroke models. J Neuroinflammation 14:248
Jin, Wei-Na; Yang, Xiaoxia; Li, Zhiguo et al. (2016) Non-invasive tracking of CD4+ T cells with a paramagnetic and fluorescent nanoparticle in brain ischemia. J Cereb Blood Flow Metab 36:1464-76
Li, Minshu; Li, Zhiguo; Ren, Honglei et al. (2016) Colony stimulating factor 1 receptor inhibition eliminates microglia and attenuates brain injury after intracerebral hemorrhage. J Cereb Blood Flow Metab :271678X16666551
Liu, Qiang; Sanai, Nader; Jin, Wei-Na et al. (2016) Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation. Nat Neurosci 19:243-52