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

Liu, Qiang; Jin, Wei�; Liu, Yaou; Shi, Kaibin; Sun, Hongzan; Zhang, Fang; Zhang, Chao; Gonzales, Rayna J.; Sheth, Kevin N; Cava, Antonio La; Shi, Fu Dong

doi:10.1016/j.immuni.2017.02.015

Cited by 150 publications

(174 citation statements)

References 54 publications

Supporting

Mentioning

158

Contrasting

Unclassified

Order By: Relevance

“…Patients suffered from ischemic stroke exhibit marked reduced spleen size and circulating NK cell numbers during acute phase of stroke onset, and these phenomena are also observed in MCAO mice [35]. In line with these findings, the present study also observed a slight decrease in the percentage of NK cells of lymphocytes in both spleen and circulating blood.…”

Section: Discussionsupporting

confidence: 90%

“…In line with these findings, the present study also observed a slight decrease in the percentage of NK cells of lymphocytes in both spleen and circulating blood. Brain ischemia activates catecholaminergic and hypothalamicpituitary-adrenal (HPA) axis, which leads to immunity suppression in the periphery [35]. It is noteworthy that BHD treatment did not affect the NK cell levels in either the spleen or blood following brain ischemia.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Buyang Huanwu Decoction Attenuates Infiltration of Natural Killer Cells and Protects Against Ischemic Brain Injury

Dou

Zhou

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Natural killer (NK) cells are among the first immune cells that respond to an ischemic insult in human brains. The infiltrated NK cells damage blood-brain barrier (BBB) and exacerbate brain infarction. Buyang Huanwu Decoction (BHD), a classic Chinese traditional herbal prescription, has long been used for the treatment of ischemic stroke. The present study investigated whether BHD can prevent brain infiltration of NK cells, attenuate BBB disruption and improve ischemic outcomes. Methods: Transient focal cerebral ischemia was induced in rats by a 60-minute middle cerebral artery occlusion, and BHD was orally administrated at the onset of reperfusion, 12 hours later, then twice daily. Assessed parameters on Day 3 after ischemia were: neurological and motor functional deficits through neurological deficit score and rotarod test, respectively; brain infarction through TTC staining; BBB integrity through Evans blue extravasation; matrix metalloproteinase-2/9 activities through gelatin zymography; tight junction protein, nuclear factor-kB (NF-kB) p65 and phospho-p65 levels through Western blotting; NK cell brain infiltration and CXCR3 levels on NK cells through flow cytometry; interferon-γ production through ELISA; CXCL10 mRNA levels through real-time PCR; CXCL10 expression and p65 nuclear translocation through immunofluorescence staining. Results: BHD markedly reduced brain infarction, improved rotarod performance, and attenuated BBB breakdown. Concurrently, BHD attenuated the upregulation of matrix metalloproteinase-2/9 activities and the degradation of tight junction proteins in the ischemic brain. Infiltration of NK cells was observed in the ischemic hemisphere, and this infiltration was blunted by treatment with BHD. BHD suppressed brain ischemia-induced interferon-γ and chemokine CXCL10 production. Furthermore, BHD significantly reduced the expression of CXCR3 on brain-infiltrated NK cells. Strikingly, BHD did not affect NK cell levels or its CXCR3 expression in the spleen or peripheral blood after brain ischemia. The nuclear translocation of NF-kB p65 and phospho-p65 in the ischemic brain was inhibited by BHD. Conclusion: Our findings suggest that BHD prevents brain infiltration of NK cells, preserves BBB integrity and eventually improves ischemic outcomes. The inhibitory effects of BHD on NK cell brain invasion may involve its ability of suppressing NF-kB-associated CXCL10-CXCR3-mediated chemotaxis. Notably, BHD only suppresses NK cells and their CXCR3 expression in the ischemic brain, but not those in periphery.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Buyang Huanwu Decoction Attenuates Infiltration of Natural Killer Cells and Protects Against Ischemic Brain Injury

Dou

Zhou

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…This result suggests that despite its potential function in bacterial defense, the number of NK cell population might not be a good indicator for stroke severity or functional deficits. Interestingly, a recent preclinical study suggested that brain ischemia could result in impaired NK cell-mediated immune defense through distinct mechanisms in the brain vs in the periphery and could therefore be differentially regulated to limit poststroke inflammation 6. In this case, the different effects of central and peripheral NK cells on stroke outcomes should be explored in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…Such lymphopenia can last for months with a gradual recovery over time. Multiple mechanisms, including the activation of sympathetic nervous system,3 the dysregulation of hypothalamic–pituitary–adrenal axis,6,7 and the release of danger-associated molecular patterns from injured brain,8 have been suggested to contribute to these immune changes after stroke.…”

Section: Introductionmentioning

confidence: 99%

Frequencies of circulating B- and T-lymphocytes as indicators for stroke outcomes

Wang¹,

Liu²,

Wang³

et al. 2017

NDT

View full text Add to dashboard Cite

BackgroundStroke has high mortality and morbidity. Biomarkers are required for to predict stroke outcomes, which could help clinicians to provide rationale approaches for patient management. The dynamic changes in circulating immune cells have been reported in stroke patients and animal models of stroke.AimThe aim of this study was to explore biomarkers to predict stroke outcomes by investigating the relationship between the frequencies of circulating immune cells and stroke outcomes.MethodsIn all, 50 acute ischemic stroke (AIS) patients were enrolled. Their blood samples were collected upon hospital admission and on day 1 and day 7 after stroke, and the leukocyte subsets were analyzed by flow cytometry. The dynamic changes in some types of immune cells in the AIS course and their correlation with clinical parameters were analyzed. Blood samples from 123 age- and gender-matched healthy subjects were used as controls.ResultsThe proportions of T-lymphocytes and NK cells in stroke patients were significantly lower than in healthy controls. The frequencies of B- and T-lymphocytes were negatively correlated with stroke severity at onset, including neurological deficits as assessed by National Institutes of Health Stroke Scale (NIHSS), and infarct volume as measured by the diffusion-weighted images (DWIs) of magnetic resonance (MR). Logistic regression analysis showed that modified Rankin scale (mRs) scores, a score system for the long-term neurological dysfunctions, were negatively correlated with the percentage of B-lymphocytes at stroke onset.ConclusionThe proportions of B- and T-lymphocytes are associated with neurological outcomes of stroke patients and might be used as an indicator for severity and prognosis of ischemic stroke.

show abstract

“…Infarct size of the ischemic stroke model was assessed with a 7 T small animal MRI previously described (Bruker Daltonics Inc., Billerica, MA, USA) (9, 27, 31). During scans, mice were placed on a regulated‐heated blanket (Bruker Daltonics Inc.) to maintain body temperature at 37.0 ± 0.5°C.…”

Section: Methodsmentioning

confidence: 99%

Activation of JAK/STAT3 restores NK‐cell function and improves immune defense after brain ischemia

et al. 2018

Self Cite

View full text Add to dashboard Cite

Stroke-induced immune suppression predisposes the host to infections and can contribute to high morbidity and mortality in stroke patients. Because ischemic stroke has a profound effect on the systemic immune response, which may explain the increased susceptibility of stroke patients to infection, an urgent need persists for a better understanding of mechanisms associated with immune suppression; new and effective treatments for stroke can then be identified. NK cells play a key role in early host defense against pathogens by killing infected cells and/or producing cytokines such as IFN-γ. Because the phenotype and function of peripheral NK cells have been widely investigated in ischemic stroke, nCounter Inflammation Gene Array Analysis was used to build immune-related gene profiles of NK cells to comprehensively analyze the molecular signature of NK cells after ischemic brain injury. We observed distinct gene expression profiles reflecting different splenic NK-cell phenotypes and functional properties across the time course of transient middle cerebral artery occlusion (MCAO). Based on gene expression and pathway-network analysis, lower expression levels of signal transducer and activator of transcription-3 (STAT3) were observed in animals with MCAO compared with sham control animals. Genetic activation of STAT3 through the introduction of STAT3 clustered regularly interspaced short palindromic repeats (CRISPR) plasmid prevented the loss of NK-cell-derived IFN-γ production after MCAO, together with reduced bacterial burden and mortality. Our data suggest that brain ischemia impairs NK-cell-mediated immune defense in the periphery, at least in part through the JAK-STAT3 pathway, which can be readdressed by modulating STAT3 activation status.-Jin, W.-N., Ducruet, A. F., Liu, Q., Shi, S. X.-Y., Waters, M., Zou, M., Sheth, K. N., Gonzales, R., Shi, F.-D. Activation of JAK/STAT3 restores NK-cell function and improves immune defense after brain ischemia.

show abstract

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

Cited by 150 publications

References 54 publications

Buyang Huanwu Decoction Attenuates Infiltration of Natural Killer Cells and Protects Against Ischemic Brain Injury

Buyang Huanwu Decoction Attenuates Infiltration of Natural Killer Cells and Protects Against Ischemic Brain Injury

Frequencies of circulating B- and T-lymphocytes as indicators for stroke outcomes

Activation of JAK/STAT3 restores NK‐cell function and improves immune defense after brain ischemia

Contact Info

Product

Resources

About