Regulatory T Cells Secrete IL10 to Suppress Neuroinflammation in Early Stage after Subarachnoid Hemorrhage.

Objective: Accumulating evidence supports neuroprotective effects of regulatory T cells (Tregs) in response to brain injury. However, the precise mechanisms underlying the beneficial effects of Tregs on suppressing neuroinflammation after subarachnoid hemorrhage (SAH) remain unclear. Methods: We performed flow cytometry to detect the infiltration of Tregs into the brain at different time points after SAH. Behavioral tests, including Adhesive and Rotarod, were performed to assess neurological deficits in mice after SAH. Bulk RNA sequencing was used to investigate the transcriptomic change of Tregs infiltrating into the brain after SAH. qPCR was performed to verify the variation of inflammatory cytokines expression in the brain after Tregs exogenous infusion. FoxP3-DTR mice and Il10 gene KO mice were used to explore the mechanism of Tregs inhibiting neuron apoptosis after infiltrating the brain following SAH onset. Results: Peripheral Tregs infiltrated into the brain one day after SAH and gradually accumulated in the hemorrhagic hemisphere. An exogenous infusion of Tregs significantly improved the neurological function of mice after SAH, while poor recovery of neurological function was observed in Tregs depletion mice. Transcriptome sequencing data suggested that the immunosuppressive function of brain-infiltrated Tregs was significantly upregulated. qPCR showed that the expression of pro-inflammatory cytokines decreased in the brain of SAH mice after exogenous Tregs infusion. Bioinformatic analysis revealed that IL-10 and other cytokines secreted by brain-infiltrated Tregs were upregulated after SAH. Moreover, exogenous infusion of Il10 gene KO Tregs did not totally improve neurological function in SAH mice. Conclusions: Tregs infiltrated into the brain in the early stage after SAH and exerted neuroprotective effect by secreting IL-10 to suppress neuroinflammation and reduce neuron apoptosis.

Single-Cell RNA Sequencing and Spatial Transcriptomics Reveal Pathogenesis of Meningeal Lymphatic Dysfunction after Experimental Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke with high mortality and disability rate. Meningeal lymphatic vessels (mLVs) are a newly discovered intracranial fluid transport system and are proven to drain extravasated erythrocytes from cerebrospinal fluid into deep cervical lymph nodes after SAH. However, many studies have reported that the structure and function of mLVs are injured in several central nervous system diseases. Whether SAH can cause mLVs injury and the underlying mechanism remain unclear. Herein, single-cell RNA sequencing and spatial transcriptomics are applied, along with in vivo/vitro experiments, to investigate the alteration of the cellular, molecular, and spatial pattern of mLVs after SAH. First, it is demonstrated that SAH induces mLVs impairment. Then, through bioinformatic analysis of sequencing data, it is discovered that thrombospondin 1 (THBS1) and S100A6 are strongly associated with SAH outcome. Furthermore, the THBS1-CD47 ligand-receptor pair is found to function as a key role in meningeal lymphatic endothelial cell apoptosis via regulating STAT3/Bcl-2 signaling. The results illustrate a landscape of injured mLVs after SAH for the first time and provide a potential therapeutic strategy for SAH based on mLVs protection by disrupting THBS1 and CD47 interaction.

New Insights of Early Brain Injury after Subarachnoid Hemorrhage: A Focus on the Caspase Family.

Spontaneous subarachnoid hemorrhage (SAH), primarily caused by ruptured intracranial aneurysms, remains a prominent clinical challenge with a high rate of mortality and morbidity worldwide. Accumulating clinical trials aiming at the prevention of cerebral vasospasm (CVS) have failed to improve the clinical outcome of patients with SAH. Therefore, a growing number of studies have shifted focus to the pathophysiological changes that occur during the periods of early brain injury (EBI). New pharmacological agents aiming to alleviate EBI have become a promising direction to improve outcomes after SAH. Caspases belong to a family of cysteine proteases with diverse functions involved in maintaining metabolism, autophagy, tissue differentiation, regeneration, and neural development. Increasing evidence shows that caspases play a critical role in brain pathology after SAH. Therefore, caspase regulation could be a potential target for SAH treatment. Herein, we provide an overview pertaining to the current knowledge on the role of caspases in EBI after SAH, and we discuss the promising therapeutic value of caspase-related agents after SAH.

Radiomic Features of the Edema Region May Contribute to Grading Meningiomas With Peritumoral Edema.

BACKGROUND: Meningiomas are frequently accompanied by peritumoral edema (PTE). The potential value of radiomic features of edema region in meningioma grading has not been investigated. PURPOSE: To investigate whether radiomic features of edema region contribute to grading meningiomas with PTE. STUDY TYPE: Retrospective. POPULATION: A total of 444 patients including 196 grade II and 248 WHO grade I meningiomas: 356 patients for training, 88 for validation. FIELD STRENGTH/SEQUENCE: A 1.5-T/3.0-T, noncontrast T1-weighted (T1WI), T2-weighted (T2WI), contrast-enhanced T1-weighted (T1CE) spin echo sequences. ASSESSMENT: A total of 851 radiomic features were extracted from each sequence on each region (tumor and edema region). These features were integrated by region respectively. Three subsets of clinical-radiomic features were constructed by joining clinical information (sex, age, tumor volume, and edema volume) and radiomic features of three regions: tumor, edema, and combined subsets. For each subset, features were filtered by the least absolute shrinkage and selection operator (LASSO) and Random Forest algorithm. Top 20 features of each subset were finally selected. STATISTICAL TESTS: Stochastic Gradient Boosting, Random Forest, and Bagged AdaBoost predictive models were built based on each subset. Discriminative abilities of models were quantified using receiver operating characteristics (ROC) and the area under the curve (AUC). A P value < 0.05 was considered statistically significant. RESULTS: Random Forest model based on combined subset (AUC [95% CI] = 0.880 [0.807-0.953]) had the best discriminative ability in grading meningiomas among the final models. The best model of edema subset and tumor subset were Random Forest model (AUC [95% CI] = 0.864 [0.791-0.938]) and Stochastic Gradient Boosting model (AUC [95% CI] = 0.844 [0.760-0.928]), respectively. DATA CONCLUSION: Radiomic features of edema region may contribute to grading meningiomas with PTE. The Random Forest model based on combined subset surpasses the best model based on tumor or edema subset regarding grading meningiomas with PTE. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Effectiveness of Postoperative Radiotherapy in Patients with Atypical Meningiomas After Gross Total Resection: Analysis of 260 Cases.

OBJECTIVE: It remains controversial whether patients with atypical meningiomas can benefit from postoperative radiotherapy (PORT) after gross total resection (GTR). This study aimed to explore the effectiveness of PORT in patients with atypical meningiomas after GTR based on our single-center data with a relatively large sample size. METHODS: Patients with atypical meningiomas who underwent GTR in our center were reviewed. Univariable and multivariable Cox proportional hazard models were conducted for survival analyses. Kaplan-Meier survival curves were generated, and 5-year progression-free survival (PFS) rates were calculated. RESULTS: This study enrolled 260 patients. PORT was not associated with PFS (P = 0.507). Sex (P = 0.006, hazard ratio 0.418, 95% confidence interval 0.224-0.781), age (P = 0.032, hazard ratio 1.032, 95% confidence interval 1.003-1.061), and tumor location (P = 0.026, hazard ratio 0.199, 95% confidence interval 0.048-0.824) were independent predictors of PFS. The 5-year PFS rate of patients receiving PORT (85.6%) was similar to that of patients not receiving PORT (84.8%). The 5-year PFS rate was 100% in patients with convexity atypical meningiomas regardless of whether or not they received PORT. CONCLUSIONS: PORT after GTR may not prolong PFS in patients with atypical meningiomas. Patients with convexity atypical meningiomas had favorable outcomes after GTR regardless of receipt of PORT.

An updated review of autophagy in ischemic stroke: From mechanisms to therapies.

Stroke is a leading cause of mortality and morbidity worldwide. Understanding the underlying mechanisms is important for developing effective therapies for treating stroke. Autophagy is a self-eating cellular catabolic pathway, which plays a crucial homeostatic role in the regulation of cell survival. Increasing evidence shows that autophagy, observed in various cell types, plays a critical role in brain pathology after ischemic stroke. Therefore, the regulation of autophagy can be a potential target for ischemic stroke treatment. In the present review, we summarize the recent progress that research has made regarding autophagy and ischemic stroke, including common signaling pathways, the role of autophagic subtypes (e.g. mitophagy, pexophagy, aggrephagy, endoplasmic reticulum-phagy, and lipophagy) in ischemic stroke, as well as the current methods for autophagy detection and potential therapeutic strategy.

The Updated Role of the Blood Brain Barrier in Subarachnoid Hemorrhage: From Basic and Clinical Studies.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke associated with high mortality and morbidity. The blood-brain-barrier (BBB) is a structure consisting primarily of cerebral microvascular endothelial cells, end feet of astrocytes, extracellular matrix, and pericytes. Post-SAH pathophysiology included early brain injury and delayed cerebral ischemia. BBB disruption was a critical mechanism of early brain injury and was associated with other pathophysiological events. These pathophysiological events may propel the development of secondary brain injury, known as delayed cerebral ischemia. Imaging advancements to measure BBB after SAH primarily focused on exploring innovative methods to predict clinical outcome, delayed cerebral ischemia, and delayed infarction related to delayed cerebral ischemia in acute periods. These predictions are based on detecting abnormal changes in BBB permeability. The parameters of BBB permeability are described by changes in computed tomography (CT) perfusion and magnetic resonance imaging (MRI). Kep seems to be a stable and sensitive indicator in CT perfusion, whereas Ktrans is a reliable parameter for dynamic contrast-enhanced MRI. Future prediction models that utilize both the volume of BBB disruption and stable parameters of BBB may be a promising direction to develop practical clinical tools. These tools could provide greater accuracy in predicting clinical outcome and risk of deterioration. Therapeutic interventional exploration targeting BBB disruption is also promising, considering the extended duration of post-SAH BBB disruption.

Raf Kinase Inhibitor Protein Preferentially Promotes TLR3-Triggered Signaling and Inflammation.

Raf kinase inhibitor protein (RKIP) protects against host immunological responses in nematodes and Drosophila Whether RKIP functions in innate immune responses in mammals remains unknown. In this article, we report that RKIP preferentially regulates the TLR3-mediated immune response in macrophages. RKIP deficiency or silencing significantly decreases polyinosinic:polycytidylic acid [Poly(I:C)]-induced IFN-ß, IL-6, and TNF-α production without affecting the counterpart induced by LPS or CpG. Compared with their wild-type counterparts, RKIP-deficient mice produce less IFN-ß, IL-6, and TNF-α in serum and display decreased lethality upon peritoneal Poly(I:C) plus d-galactosamine injection. Mechanistically, RKIP interacts with TBK1 and promotes the Poly(I:C)-induced TANK-binding kinase 1/IRF3 activation. Simultaneously, RKIP enhances the Poly(I:C)-induced interaction between TGF-ß-activated kinase 1 and MAPK kinase 3 (MKK3), thus promoting MKK3/6 and p38 activation. We further demonstrated that Poly(I:C) treatment, but not LPS treatment, induces RKIP phosphorylation at S109. This action is required for RKIP to promote TANK-binding kinase 1 activation, as well as the interaction between TGF-ß-activated kinase 1 and MKK3, which lead to activation of the downstream IRF3 and p38, respectively. Therefore, RKIP acts as a positive-feedback regulator of the TLR3-induced inflammatory response and may be a potential therapeutic target for inflammatory disease.