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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.

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.

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.

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12975-016-0496-0) contains supplementary material, which is available to authorized users.

ObjectiveThe present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window.MethodsThis 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.ResultsEach 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.InterpretationFingolimod 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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Intracerebral hemorrhage (ICH) is a devastating disease, which accounts for ≈10% to 15% of strokes with high mortality and morbidity.1,2 Effective treatments for ICH remain sparse.1 Accumulating evidence has demonstrated that brain inflammation provoked by microglia and infiltrating lymphocytes exacerbates ICH-induced brain injury.3 After ICH, brain-intrinsic microglia are the first immune responder and followed by inflammatory infiltrates such as neutrophils, monocytes, macrophages, and subsets of lymphocytes. 4,5 Activation of these cellular components together with factors they produce and cell death products, further contribute to brain inflammation, which results in the development of perihematomal edema.3-7 Perihematomal edema can aggravate the mass effect and secondary brain injury through subsequent oligemia and inflammatory insults.1,8 Edema, as a surrogate marker for inflammation in ICH, 1,9,10 and the persistence of perihematomal edema after ictus makes it amenable for intervention.1 Thus, targeting inflammation could be a viable approach for treating ICH.Sphingosine-1-phosphate (S1P) is a ligand for 5 G-proteincoupled receptors: S1P receptors 1 to 5 (S1PR1-5) are responsible for numerous cell-intrinsic and extrinsic activities. 11,12 Fingolimod (FTY720, Glenya), an oral therapy for multiple sclerosis (MS), is a S1PR modulator that binds to S1PR1, 3, 4, and 5. The beneficial effects of fingolimod in MS may be mediated by S1PR1 expressed on lymphocytes, vascular endothelia, neurons, and glia.11 Recent preclinical and clinical studies have demonstrated that fingolimod can attenuate neurodeficits and brain edema in ICH. [13][14][15][16][17][18] However, it remains unclear whether immune modulations via S1PR1 are sufficient for fingolimod to provide 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 th...