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.
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.
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.
Approaches for the effective management of acute stroke are sparse, and many measures for brain protection fail. However, our ability to modulate the immune system and modify the progression of ...multiple sclerosis is increasing. As a result, immune interventions are currently being explored as therapeutic interventions in acute stroke. In this Review, we compare the immunological features of acute stroke with those of multiple sclerosis, identify unique immunological features of stroke, and consider the evidence for immune interventions. In patients with acute stroke, microglial activation and cell death products trigger an inflammatory cascade that damages vessels and the parenchyma within minutes to hours of the ischaemia or haemorrhage. Immune interventions that restrict brain inflammation, vascular permeability and tissue oedema must be administered rapidly to reduce acute immune-mediated destruction and to avoid subsequent immunosuppression. Preliminary results suggest that the use of drugs that modify disease in multiple sclerosis might accomplish these goals in ischaemic and haemorrhagic stroke. Further elucidation of the immune mechanisms involved in stroke is likely to lead to successful immune interventions.
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.,LaCava,A.,Sheth,K.N.,Shi,F.‐D.Organ‐andcell‐specificimmune responses are associated with the outcomes of intracerebral hemorrhage. FASEB J. 32,220‐229 (2018). www.fasebj.org
ABSTRACT
Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. After ICH, the immediate infiltration of leukocytes and activation of microglia are accompanied by a ...rapid up‐regulation of the 18‐kDa translocator protein (TSPO). TSPO ligands have shown anti‐inflammatory and neuroprotective properties in models of CNS injury. In this study, we determined the impact of a TSPO ligand, etifoxine, on brain injury and inflammation in 2 mouse models of ICH. TSPO was up‐regulated in Iba1+ cells from brains of patients with ICH and in CD11b+CD45int cells from mice subjected to collagenase‐induced ICH. Etifoxine significantly reduced neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In collagenase‐induced ICH mice, the protection of etifoxine was associated with reduced leukocyte infiltration into the brain and microglial production of IL‐6 and TNF‐α. Etifoxine improved blood–brain barrier integrity and diminished cell death. Notably, the protective effect of etifoxine was abolished in mice depleted of microglia by using a colony‐stimulating factor 1 receptor inhibitor. These results indicate that the TSPO ligand etifoxine attenuates brain injury and inflammation after ICH. TSPO may be a viable therapeutic target that requires further investigations in ICH.—Li, M., Ren, H., Sheth, K. N., Shi, F.‐D., Liu, Q. A TSPO ligand attenuates brain injury after intracerebral hemorrhage. FASEB J. 31, 3278–3287 (2017). www.fasebj.org
In 2020, inebilizumab was approved for the treatment of neuromyelitis optica spectrum disorder by the US Food and Drug Administration, following results from the N-MOmentum trial.3 During the ...relatively short (6·5 months) randomised controlled period, only 21 (12%) of 174 participants receiving inebilizumab had an inflammatory attack compared with 22 (39%) of 56 participants in the placebo group.3 In The Lancet Neurology, Bruce A C Cree and colleagues4 now report end-of-study data from the N-MOmentum trial, which includes up to 4 years of follow-up data from the randomised controlled period and an open-label period. The adjusted annualised attack rates decreased from mean 1·72 (SD 1·54) at baseline in the open-label period to 0·092 (95% CI 0·067–0·127) at 4-year follow-up.4 Additional benefits evident among individuals receiving inebilizumab included less worsening of disability (as measured by the Expanded Disability Status Scale), fewer disease-related hospitalisations, and fewer new MRI lesions, as well as attenuation of neuropathic pain. ...notably, the high efficacy of B-cell-depletion therapy with rituximab, ocrelizumab, or ofatumumab in multiple sclerosis suggests that the benefit of B-cell-depletion therapy might not depend entirely on the removal of the antibody-producing function of B cells.
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
Azathioprine is used as a first-line treatment to prevent relapses of neuromyelitis optica spectrum disorder (NMOSD). Tocilizumab has been reported to reduce NMOSD disease activity in retrospective ...case reports. We aimed to compare the safety and efficacy of tocilizumab and azathioprine in patients with highly relapsing NMOSD.
We did an open-label, multicentre, randomised, phase 2 trial at six hospitals in China. We recruited adult patients (aged ≥18 years) with highly relapsing NMOSD diagnosed according to 2015 International Panel for Neuromyelitis Optica Diagnosis criteria, who had an Expanded Disability Status Scale (EDSS) score of 7·5 or lower, and had a history of at least two clinical relapses during the previous 12 months or three relapses during the previous 24 months with at least one relapse within the previous 12 months. Patients were randomly assigned (1:1) to intravenous tocilizumab (8 mg/kg every 4 weeks) or oral azathioprine (2–3 mg/kg per day) by an independent statistician using computer-generated randomisation software with permuted blocks of four. The central review committee, EDSS raters, laboratory personnel, and radiologists were masked to the treatment assignment, but investigators and patients were aware of treatment allocation. The minimum planned duration of treatment was 60 weeks following randomisation. The primary outcome was time to first relapse in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, and the per-protocol population, which included all patients who used azathioprine or tocilizumab as monotherapy. For the analyses of the primary outcome, the patients were prespecified into two subgroups according to concomitant autoimmune disease status. Safety was assessed in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03350633.
Between Nov 1, 2017, and Aug 3, 2018, we enrolled 118 patients, of whom 59 were randomly assigned to tocilizumab and 59 were randomly assigned to azathioprine. All 118 patients received one dose of study drug and were included in the full analysis set. 108 participants were included in the per-protocol analysis (56 in the tocilizumab group and 52 in the azathioprine group). In the full analysis set, median time to the first relapse was longer in the tocilizumab group than the azathioprine group (78·9 weeks IQR 58·3–90·6 vs 56·7 32·9–81·7 weeks; p=0·0026). Eight (14%) of 59 patients in the tocilizumab group and 28 (47%) of 59 patients in the azathioprine group had a relapse at the end of the study (hazard ratio HR 0·236 95% CI 0·107–0·518; p<0·0001). In the per-protocol analysis, 50 (89%) of 56 patients in the tocilizumab group were relapse-free compared with 29 (56%) of 52 patients in the azathioprine group at the end of the study (HR 0·188 95% CI 0·076–0·463; p<0·0001); the median time to first relapse was also longer in the tocilizumab group than the azathioprine group (67·2 weeks IQR 47·9–77·9 vs 38·0 23·6–64·9; p<0·0001). In the prespecified subgroup analysis of the full analysis set stratified by concomitant autoimmune diseases, among patients without concomitant autoimmune diseases, three (9%) of 34 patients in the tocilizumab group and 13 (35%) of 37 patients in the azathioprine group had relapsed by the end of the study. Among patients with concomitant autoimmune diseases, a lower proportion of patients in the tocilizumab group had a relapse than in the azathioprine group (five 20% of 25 patients vs 15 68% of 22 patients; HR 0·192 95% CI 0·070–0·531; p=0·0004). 57 (97%) of 59 patients in the tocilizumab group and 56 (95%) of 59 patients in the azathioprine group had adverse events. Treatment-associated adverse events occurred in 36 (61%) of 59 tocilizumab-treated patients and 49 (83%) of 59 azathioprine-treated patients. One death (2%) occurred in the tocilizumab group and one (2%) in the azathioprine group, but neither of the deaths were treatment-related.
Tocilizumab significantly reduced the risk of a subsequent NMOSD relapse compared with azathioprine. Tocilizumab might therefore be another safe and effective treatment to prevent relapses in patients with NMOSD.
Tianjin Medical University, Advanced Innovation Center for Human Brain Protection, National Key Research and Development Program of China, National Science Foundation of China.
ABSTRACT
Inflammatory factors secreted by microglia play an important role in focal ischemic stroke. The mammalian target of rapamycin (mTOR) pathway is a known regulator of immune responses, but the ...role that mTORC1 signaling plays in poststroke neuroinflammation is not clear. To explore the relationship between microglial action in the mTORC1 pathway and the impact on stroke, we administered the mTORC1 inhibitors sirolimus and everolimus to mice. Presumably, disrupting the mTORC1 pathway after focal ischemic stroke should clarify the subsequent activity of microglia. For that purpose, we generated mice deficient in the regulatory associated protein of mTOR (Raptor) in microglia, whose mTORC1 signaling was blocked, by crossing Raptor loxed (Raptorflox/flox) mice with CX3CR1CreER mice, which express Cre recombinase under the control of the CX3C chemokine receptor 1 promoter. mTORC1 blockade reduced lesion size, improved motor function, dramatically decreased production of pro‐inflammatory cytokines and chemokines, and reduced the number of M1 type microglia. Thus, mTORC1 blockade apparently attenuated behavioral deficits and poststroke inflammation after middle cerebral artery occlusion by preventing microglia polarization toward the M1 type.—Li, D., Wang, C., Yao, Y., Chen, L., Liu, G., Zhang, R., Liu, Q., Shi, F.‐D., Hao, J. mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type. FASEB J. 30, 3388–3399 (2016). www.fasebj.org
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