Publications by authors named "Kaibin Shi"

20 Publications

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Brain injury instructs bone marrow cellular lineage destination to reduce neuroinflammation.

Sci Transl Med 2021 Apr;13(589)

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.

Acute brain injury mobilizes circulating leukocytes to transmigrate into the perivascular space and brain parenchyma. This process amplifies neural injury. Bone marrow hematopoiesis replenishes the exhausted peripheral leukocyte pools. However, it is not known whether brain injury influences the development of bone marrow lineages and how altered hematopoietic cell lineages affect neurological outcome. Here, we showed that bone marrow hematopoietic stem cells (HSCs) can be swiftly skewed toward the myeloid lineage in patients with intracerebral hemorrhage (ICH) and experimental ICH models. Lineage tracing revealed a predominantly augmented hematopoiesis of Ly6C monocytes infiltrating the ICH brain, where they generated alternatively activated macrophages and suppressed neuroinflammation and brain injury. The ICH brain uses β3-adrenergic innervation that involves cell division cycle 42 to promote bone marrow hematopoiesis of Ly6C monocytes, which could be further potentiated by the U.S. Food and Drug Administration-approved β3-adrenergic agonist mirabegron. Our results suggest that brain injury modulates HSC lineage development to curb distal brain inflammation, implicating the bone marrow as a unique niche for self-protective neuroimmune interaction that might be exploited to obtain therapeutic effects.
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http://dx.doi.org/10.1126/scitranslmed.abc7029DOI Listing
April 2021

Low-dose rituximab treatment for new-onset generalized myasthenia gravis.

J Neuroimmunol 2021 May 24;354:577528. Epub 2021 Feb 24.

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China. Electronic address:

The aim of this retrospective case series study was to evaluate the response and durability of rituximab in patients with new-onset acetylcholine receptor positive (AChR +) generalized myasthenia gravis (MG). Patients were initiated with low-dose rituximab treatment within 3.5 months of onset without concomitant oral immunosuppressants. Seventeen patients (89%) remained relapse-free with a mean follow-up of 51.3 months. Clinical improvement was observed in parallel with the maintenance of low-dose corticosteroids or the complete discontinuation of corticosteroids. Long-term depletion of B cells with low-dose rituximab treatment has shown favorable efficacy and tolerance in reducing disease activity for AChR+ generalized MG.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577528DOI Listing
May 2021

Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition.

Nat Neurosci 2021 01 30;24(1):61-73. Epub 2020 Nov 30.

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.

Normal aging is accompanied by escalating systemic inflammation. Yet the potential impact of immune homeostasis on neurogenesis and cognitive decline during brain aging have not been previously addressed. Here we report that natural killer (NK) cells of the innate immune system reside in the dentate gyrus neurogenic niche of aged brains in humans and mice. In situ expansion of these cells contributes to their abundance, which dramatically exceeds that of other immune subsets. Neuroblasts within the aged dentate gyrus display a senescence-associated secretory phenotype and reinforce NK cell activities and surveillance functions, which result in NK cell elimination of aged neuroblasts. Genetic or antibody-mediated depletion of NK cells leads to sustained improvements in neurogenesis and cognitive function during normal aging. These results demonstrate that NK cell accumulation in the aging brain impairs neurogenesis, which may serve as a therapeutic target to improve cognition in the aged population.
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http://dx.doi.org/10.1038/s41593-020-00745-wDOI Listing
January 2021

tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke.

Circ Res 2021 Jan 19;128(1):62-75. Epub 2020 Oct 19.

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, China (K.S., M.Z., D.-M.J., X.Y., Q.L., F.-D.S.).

Rationale: Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation.

Objective: We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke.

Methods And Results: Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis.

Conclusions: Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317596DOI Listing
January 2021

Cortical Thinning and Ventricle Enlargement in Neuromyelitis Optica Spectrum Disorders.

Front Neurol 2020 27;11:872. Epub 2020 Aug 27.

Center for Neuroinflammation, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

In neuromyelitis optica spectrum disorders (NMOSDs), inflammation is not the sole driver of accumulation of disability; neurodegeneration is another important pathological process. We aim to explore different patterns of cortical atrophy and ventricular enlargement in NMOSD. We retrospectively analyzed a cohort of 230 subjects, comprising 55 healthy controls (HCs), 85 multiple sclerosis (MS), and 90 NMOSD patients from Tianjin Medical University General Hospital and Beijing Tiantan Hospital. Different compartments of the brain (total gray, cortex, subcortex gray, and ventricle volume) were evaluated with the FreeSurfer. Multiple linear regressions were adopted to explore associations between cortex volume and predict factors. Compared with HCs, NMOSD, and MS displayed an enlarged lateral and third ventricle ( < 0.001), whereas expansion of the fourth ventricle was observed in MS rather than NMOSD ( = 0.321). MS and NMOSD patients exhibited cortical thinning in comparison with HCs. However, pronounced cortical atrophy were only significant in pre-cuneus, parahippocampal, and lateral occipital lobe between MS and NMOSD. Patients with NMOSD had decreased local gyrification index in orbitofrontal and pre-cuneus lobe, and reduced pial surface area. Linear regression analysis revealed cortex volume were predicated by advanced age (standardized β = -0.404, = 0.001) as well as prolonged disease history (standardized β = -0.311, = 0.006). NMOSD exhibited global cortex atrophy with enlarged lateral and third ventricles. Moreover, cortex volume is associated with age and disease duration.
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http://dx.doi.org/10.3389/fneur.2020.00872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481470PMC
August 2020

IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage.

Stroke 2020 03 5;51(3):967-974. Epub 2020 Feb 5.

From the Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (S.X.S., K.S., K.W., A.F.D., Q.L.).

Background and Purpose- Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods- Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results- In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15 mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15 mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1β, and TNF-α is markedly increased in GFAP-IL-15 mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15 mice. Conclusions- Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.
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http://dx.doi.org/10.1161/STROKEAHA.119.028638DOI Listing
March 2020

Dl-3-n-butylphthalide Reduces Neurovascular Inflammation and Ischemic Brain Injury in Mice.

Aging Dis 2019 Oct 1;10(5):964-976. Epub 2019 Oct 1.

1Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.

Dl-3-n-butylphthalide (NBP) is a synthetic compound that has been approved for the treatment of ischemic stroke in China. The mechanisms underlying the treatment efficacy of NBP have been reported in multiple studies and remain controversial. Here, we show that NBP treatment attenuated ischemic brain injury in mice subjected to transient middle cerebral artery occlusion or photothrombosis-induced permanent cerebral ischemia. NBP induced downregulation of intercellular adhesion molecule 1 and protease-activated receptor 1 in cerebrovascular endothelial cells after cerebral ischemia and reperfusion. This effect was associated with the reduced brain infiltration of myeloid cells and improved cerebral blood flow after reperfusion. The beneficial effects of NBP were diminished in mice subjected to the depletion of Gr1 myeloid cells before brain ischemia. Therefore, the restriction of neurovascular inflammation is a key mode of action for NBP in ischemic stroke.
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http://dx.doi.org/10.14336/AD.2019.0608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764730PMC
October 2019

Global brain inflammation in stroke.

Lancet Neurol 2019 11 8;18(11):1058-1066. Epub 2019 Jul 8.

China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Tianjin Medical University General Hospital, Tianjin, China. Electronic address:

Stroke, including acute ischaemic stroke and intracerebral haemorrhage, results in neuronal cell death and the release of factors such as damage-associated molecular patterns (DAMPs) that elicit localised inflammation in the injured brain region. Such focal brain inflammation aggravates secondary brain injury by exacerbating blood-brain barrier damage, microvascular failure, brain oedema, oxidative stress, and by directly inducing neuronal cell death. In addition to inflammation localised to the injured brain region, a growing body of evidence suggests that inflammatory responses after a stroke occur and persist throughout the entire brain. Global brain inflammation might continuously shape the evolving pathology after a stroke and affect the patients' long-term neurological outcome. Future efforts towards understanding the mechanisms governing the emergence of so-called global brain inflammation would facilitate modulation of this inflammation as a potential therapeutic strategy for stroke.
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http://dx.doi.org/10.1016/S1474-4422(19)30078-XDOI Listing
November 2019

Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage.

FASEB J 2019 08 30;33(8):9616-9626. Epub 2019 May 30.

Departments of Neurology and Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA.

Delayed cognitive decline commonly occurs following intracerebral hemorrhage (ICH), but the mechanisms underlying this phenomenon remain obscure. We therefore investigated the potential mechanisms responsible for impaired cognitive function in a mouse collagenase model of ICH. Following recovery of motor and sensory deficits in the chronic phase of ICH, we noted significant cognitive impairment, which was assessed by the Morris water maze. This finding was accompanied by reduced dendrite spine density of ipsilateral hippocampal CA1 neurons. Reduced synaptic plasticity, manifested by impaired long-term potentiation in hippocampal neurons, was also evident in both ipsilateral and contralateral hemispheres, suggesting that ICH also induces functional alterations in distal brain regions remote from the site of injury. In addition, the accumulation of microglia, infiltration of peripheral immune cells, and generation of reactive oxygen species were observed in both contralateral and ipsilateral hemispheres up to 5 wk post-ICH. Furthermore, depletion of microglia using PLX3397, which inhibits colony stimulating factor 1 receptor, ameliorated this delayed cognitive impairment. Collectively, these results suggest that persistent and diffuse brain inflammation may contribute to cognitive impairment in the chronic stage of ICH recovery.-Shi, E., Shi, K., Qiu, S., Sheth, K. N., Lawton, M. T., Ducruet, A. F. Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage.
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http://dx.doi.org/10.1096/fj.201900257RDOI Listing
August 2019

Dissemination of brain inflammation in traumatic brain injury.

Cell Mol Immunol 2019 06 7;16(6):523-530. Epub 2019 Mar 7.

Departments of Neurology and Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.

Traumatic brain injury (TBI) is recognized as a global health problem due to its increasing occurrence, challenging treatment, and persistent impacts on brain pathophysiology. Neural cell death in patients with TBI swiftly causes inflammation in the injured brain areas, which is recognized as focal brain inflammation. Focal brain inflammation causes secondary brain injury by exacerbating brain edema and neuronal death, while also exerting divergent beneficial effects, such as sealing the damaged limitans and removing cellular debris. Recent evidence from patients with TBI and studies on animal models suggest that brain inflammation after TBI is not only restricted to the focal lesion but also disseminates to remote areas of the brain. The dissemination of inflammation has been detected within days after the primary injury and persists chronically. This state of inflammation may be related to remote complications of TBI in patients, such as hyperthermia and hypopituitarism, and may lead to progressive neurodegeneration, such as chronic traumatic encephalopathy. Future studies should focus on understanding the mechanisms that govern the initiation and propagation of brain inflammation after TBI and its impacts on post-trauma brain pathology.
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http://dx.doi.org/10.1038/s41423-019-0213-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804599PMC
June 2019

Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow.

Ann Neurol 2018 11 2;84(5):717-728. Epub 2018 Nov 2.

Center for Neuroinflammation, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Objective: The present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window.

Methods: This was a prospective, randomized, open-label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingolimod. All patients underwent pretreatment and 24-hour noncontrast computed tomography (CT)/perfusion CT/CT angiography. The coprimary endpoints were the decrease of National Institutes of Health Stroke Scale scores over 24 hours and the favorable shift of modified Rankin Scale score (mRS) distribution at day 90. Exploratory outcomes included vessel recanalization, anterograde reperfusion, and retrograde reperfusion of collateral flow.

Results: Each treatment group included 23 patients. Compared with alteplase alone, patients receiving fingolimod plus alteplase exhibited better early clinical improvement at 24 hours and a favorable shift of mRS distribution at day 90. In addition, patients who received fingolimod and alteplase exhibited a greater reduction in the perfusion lesion accompanied by suppressed infarct growth by 24 hours. Fingolimod in conjunction with alteplase significantly improved anterograde reperfusion of downstream territory and prevented the failure of retrograde reperfusion from collateral circulation.

Interpretation: Fingolimod may enhance the efficacy of alteplase administration in the 4.5- to 6-hour time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow. These findings are instructive for the design of future trials of recanalization therapies in extended time windows. Ann Neurol 2018;84:725-736.
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http://dx.doi.org/10.1002/ana.25352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282815PMC
November 2018

Stroke-induced immunosuppression and poststroke infection.

Stroke Vasc Neurol 2018 Mar 12;3(1):34-41. Epub 2018 Jan 12.

Departments of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.

Infections occur commonly after stroke and are strongly associated with an unfavourable functional outcome of these patients. Approaches for effective management of poststroke infection remain scarce, presenting an urgent need for preventive anti-infection strategies for patients who have suffered a stroke. Emerging evidence indicates that stroke impairs systemic immune responses and increases the susceptibility to infections, suggesting that the modification of impaired immune defence could be beneficial. In this review, we summarised previous attempts to prevent poststroke infections using prophylactic antibiotics and the current understanding of stroke-induced immunosuppression. Further elucidation of the immune mechanisms of stroke will pave the way to tailored design of new treatment to combat poststroke infection via modifying the immune system.
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http://dx.doi.org/10.1136/svn-2017-000123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870641PMC
March 2018

Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage.

FASEB J 2018 01 6;32(1):220-229. Epub 2017 Sep 6.

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China;

Severe brain injury significantly influences immune responses; however, the levels at which this influence occurs and which neurogenic pathways are involved are not well defined. Here, we used MRI to measure spleen volume and tissue diffusion changes in patients with intracerebral hemorrhage (ICH). We observed increased capillary exchange and spleen shrinkage by d 3 post-ICH, with recovery by d 14. The extent of spleen shrinkage was associated with brain hematoma size, and a reduced progression of perihematomal edema was observed in the presence of severe spleen shrinkage. At the cellular level, lymphopenia was present in patients with ICH at admission and persisted up to 14 d. Lymphopenia did not parallel the observed spleen alteration. In addition, patients with ICH with infection had significant deficiencies of T and NK cells and poor functional outcomes. Finally, in mouse models of ICH, spleen shrinkage could be related to innervations from adrenergic input and the hypothalamus-pituitary-adrenal (HPA) axis. In sum, the profound impact of ICH on the immune system involves the coordinated actions of sympathetic innervation and the HPA axis, which modulate spleen shrinkage and cellular immunity.-Zhang, J., Shi, K., Li, Z., Li, M., Han, Y., Wang, L., Zhang, Z., Yu, C., Zhang, F., Song, L., Dong, J.-F., La Cava, A., Sheth, K. N., Shi, F.-D. Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage.
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http://dx.doi.org/10.1096/fj.201700324RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731128PMC
January 2018

Bidirectional degeneration in the visual pathway in neuromyelitis optica spectrum disorder (NMOSD).

Mult Scler 2018 10 21;24(12):1585-1593. Epub 2017 Aug 21.

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China/Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.

Objective: This study aims to investigate whether bidirectional degeneration occurs within the visual pathway and, if so, the extent of such changes in neuromyelitis optica spectrum disorder (NMOSD).

Methods: In total, 36 NMOSD and 24 healthy controls (HCs) were enrolled. Three-dimensional T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging were used to analyze damage to the posterior visual pathway. Damage to the anterior visual pathway was measured by optical coherence tomography.

Results: In total, 24 NMOSD with prior optic neuritis (NMOON) patients showed significant reduction of peripapillary retinal nerve fiber layer, inner and outer retinal thickness, lateral geniculate nucleus volume, primary visual cortex volume, and decreased integrity of optic radiations, compared with 12 NMOSD without prior optic neuritis (NMONON) patients and 24 HCs. In NMONON, only the inner retinal thickness and the integrity of optic radiations were significantly reduced in comparison with HCs. Moreover, patients with optic neuritis showed severe bidirectional degeneration, the loss of the RNFL was greater than the atrophy of V1.

Conclusion: Our study indicated the presence of trans-synaptic degeneration in NMOSD. Damage to the inner retina and optic radiations can be observed even in NMONON. After an episode of optic neuritis, the anterior visual pathway damage is greater than the posterior visual pathway damage.
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http://dx.doi.org/10.1177/1352458517727604DOI Listing
October 2018

Low expression of complement inhibitory protein CD59 contributes to humoral autoimmunity against astrocytes.

Brain Behav Immun 2017 Oct 2;65:173-182. Epub 2017 May 2.

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710000, China. Electronic address:

Neuromyelitis optica spectrum disorder is primarily an anti-aquaporin 4 autoantibody-mediated, central nervous system-restricted channelopathy. Patients frequently develop central nervous system-restricted lesions even though autoantigen aquaporin 4 in neuromyelitis optica spectrum disorder is broadly distributed in the central nervous system and peripheral organs. The cause of such tissue-specific immune response remains largely unknown. We confirmed here that CD59, an inhibitory regulator of the complement membrane attack complex, is expressed and co-localized with aquaporin 4 in peripheral organs but is only minimally expressed in astrocytes in the central nervous system. In addition, we further found that CD59 overexpression in mouse brains decreased demyelination, blocked the loss of astrocytes and aquaporin 4, and inhibited membrane attack complex formation and infiltration of inflammatory cells. Inactivation of CD59 in mouse peripheral aquaporin 4-expressing cells and tissues led to complement-dependent cytotoxicity. In accordance with the mouse data, human samples presented higher expression of CD59 in many aquaporin 4-expressing peripheral tissues but not in astrocytes. Silencing or blocking CD59 in aquaporin 4-expressing human tracheal epithelial and skeletal muscle cells induced membrane attack complex formation and cytotoxicity, which suggests a protective role of CD59 in anti-aquaporin 4 antibodies-mediated complement toxicity. Our findings suggest that low CD59 expression in astrocytes may contribute to central nervous system-restricted lesions in neuromyelitis optica spectrum disorder. Restoring CD59 expression in astrocytes may serve as a novel therapeutic target of neuromyelitis optica spectrum disorder.
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http://dx.doi.org/10.1016/j.bbi.2017.04.023DOI Listing
October 2017

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

Immunity 2017 03 14;46(3):474-487. Epub 2017 Mar 14.

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:

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.
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http://dx.doi.org/10.1016/j.immuni.2017.02.015DOI Listing
March 2017

CFHR1-Modified Neural Stem Cells Ameliorated Brain Injury in a Mouse Model of Neuromyelitis Optica Spectrum Disorders.

J Immunol 2016 11 26;197(9):3471-3480. Epub 2016 Sep 26.

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China;

A major hurdle for effective stem cell therapy is ongoing inflammation in the target organ. Reconditioning the lesion microenvironment may be an effective way to promote stem cell therapy. In this study, we showed that engineered neural stem cells (NSCs) with complement factor H-related protein 1, a complement inhibitor protein, can attenuate inflammatory infiltration and immune-mediated damage of astrocytes, an important pathogenic progress in patients with neuromyelitis optica spectrum disorders. Furthermore, we demonstrated that transplantation of the complement factor H-related protein 1-modified NSCs effectively blocked the complement activation cascade and inhibited formation of the membrane attack complex, thus contributing to the protection of endogenous and transplanted NSC-differentiated astrocytes. Therefore, manipulation of the lesion microenvironment contributes to a more effective cell replacement therapeutic strategy for autoimmune diseases of the CNS.
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http://dx.doi.org/10.4049/jimmunol.1600135DOI Listing
November 2016

Dimethyl Fumarate and Monomethyl Fumarate Promote Post-Ischemic Recovery in Mice.

Transl Stroke Res 2016 12 10;7(6):535-547. Epub 2016 Sep 10.

Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.

Oxidative stress plays an important role in cerebral ischemia-reperfusion injury. Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) are antioxidant agents that can activate the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and induce the expression of antioxidant proteins. Here, we evaluated the impact of DMF and MMF on ischemia-induced brain injury and whether the Nrf2 pathway mediates the effects provided by DMF and MMF in cerebral ischemia-reperfusion injury. Using a mouse model of transient focal brain ischemia, we show that DMF and MMF significantly reduce neurological deficits, infarct volume, brain edema, and cell death. Further, DMF and MMF suppress glial activation following brain ischemia. Importantly, the protection of DMF and MMF was mostly evident during the subacute stage and was abolished in Nrf2 mice, indicating that the Nrf2 pathway is required for the beneficial effects of DMF and MMF. Together, our data indicate that DMF and MMF have therapeutic potential in cerebral ischemia-reperfusion injury and their protective role is likely mediated by the Nrf2 pathway.
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http://dx.doi.org/10.1007/s12975-016-0496-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065588PMC
December 2016

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage.

Stroke 2016 07 12;47(7):1899-906. Epub 2016 May 12.

From the Departments of Neurology (N.S., Y.S., K.S., Y.F., J.H., Q.L., F.-D.S.) and Radiology (W.H.), Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ (N.S., K.W., Q.L., F.-D.S.); Department of Neurology, Yale University School of Medicine, New Haven, CT (K.N.S.); and Department of Clinical Research and Multiple Sclerosis Center, Neurology and Neuroscience Associates, Unity Health Network, Akron, OH (D.H.).

Background And Purpose: Preclinical studies and a proof-of-concept clinical study have shown that sphingosine-1-phosphate receptor (S1PR) modulator, fingolimod, improves the clinical outcome of intracerebral hemorrhage (ICH). However, the specific subtype of the S1PRs through which immune modulation provides protection in ICH remains unclear. In addition, fingolimod-induced adverse effects could limit its use in patients with stroke because of interactions with other S1PR subtypes, particularly with S1PR3. RP101075 is a selective S1PR1 agonist with superior cardiovascular safety profile. In this study, we investigated the impact of RP101075 treatment in a mouse model of ICH.

Methods: ICH was induced by injection of autologous blood in 294 male C57BL/6J and Rag2(-/-) mice. ICH mice randomly received vehicle, RP101075, or RP101075 plus S1PR1 antagonist W146 by daily oral gavage for three consecutive days, starting from 30 minutes after surgery. Neurodeficits, brain edema, brain infiltration of immune cells, blood-brain barrier integrity, and cell death were assessed after ICH.

Results: RP101075 significantly attenuated neurological deficits and reduced brain edema in ICH mice. W146 blocked the effects of RP101075 on neurodeficits and brain edema. RP101075 reduced the counts of brain-infiltrating lymphocytes, neutrophils, and microglia, as well as cytokine expression after ICH. Enhanced blood-brain barrier integrity and alleviated neuronal death were also seen in ICH mice after RP101075 treatment.

Conclusions: S1PR1 modulation via RP101075 provides protection in experimental ICH. Together with the advantageous pharmacological features of RP101075, these results warrant further investigations of its mechanisms of action and translational values in ICH patients.
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http://dx.doi.org/10.1161/STROKEAHA.115.012236DOI Listing
July 2016

Autoantibody to MOG suggests two distinct clinical subtypes of NMOSD.

Sci China Life Sci 2016 Dec 26;59(12):1270-1281. Epub 2016 Feb 26.

Departments of Neurology and Immunology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.

We characterized a unique group of patients with neuromyelitis optica spectrum disorder (NMOSD) who carried autoantibodies of aquaporin-4 (AQP4) and myelin-oligodendrocyte glycoprotein (MOG). Among the 125 NMOSD patients, 10 (8.0%) were AQP4- and MOG-ab double positive, and 14 (11.2%) were MOG-ab single positive. The double-positive patients had a multiphase disease course with a high annual relapse rate (P=0.0431), and severe residual disability (P>0.0001). Of the double- positive patients, 70% had MS-like brain lesions, more severe edematous, multifocal regions on spinal magnetic resonance imaging (MRI), pronounced decreases of retinal nerve fiber layer thickness and atrophy of optic nerves. In contrast, patients with only MOG-ab had a higher ratio of monophasic disease course and mild residual disability. Spinal cord MRI illustrated multifocal cord lesions with mild edema, and brain MRIs showed more lesions around lateral ventricles. NMOSD patients carrying both autoantibodies to AQP4 and MOG existed and exhibited combined features of prototypic NMO and relapsing- remitting form of MS, whereas NMOSD with antibodies to MOG only exhibited an "intermediate" phenotype between NMOSD and MS. Our study suggests that antibodies against MOG might be pathogenic in NMOSD patients and that determination of anti-MOG antibodies maybe instructive for management of NMOSD patients.
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http://dx.doi.org/10.1007/s11427-015-4997-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101174PMC
December 2016