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Stroke is the second leading cause of global death and is characterized by high rates of mortality and disability. Oxidative stress is accompanied by other pathological processes that together lead to secondary brain damage in stroke. As the major component of the brain, glial cells play an important role in normal brain development and pathological injury processes. Multiple connections exist in the pathophysiological changes of reactive oxygen species (ROS) metabolism and glia cell activation. Astrocytes and microglia are rapidly activated after stroke, generating large amounts of ROS via mitochondrial and NADPH oxidase pathways, causing oxidative damage to the glial cells themselves and neurons. Meanwhile, ROS cause alterations in glial cell morphology and function, and mediate their role in pathological processes, such as neuroinflammation, excitotoxicity, and blood-brain barrier damage. In contrast, glial cells protect the Central Nervous System (CNS) from oxidative damage by synthesizing antioxidants and regulating the Nuclear factor E2-related factor 2 (Nrf2) pathway, among others. Although numerous previous studies have focused on the immune function of glial cells, little attention has been paid to the role of glial cells in oxidative stress. In this paper, we discuss the adverse consequences of ROS production and oxidative-antioxidant imbalance after stroke. In addition, we further describe the biological role of glial cells in oxidative stress after stroke, and we describe potential therapeutic tools based on glia cells.

Background Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial/macrophage activation and neuroinflammation are key cellular events following TBI, but the regulatory and functional mechanisms are still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, regulates multiple features of microglial/macrophage physiology. However, its function in regulating the innate immune response and microglial/macrophage M1/M2 polarization in TBI has not been addressed. The present study aimed to evaluate the role of Mer in regulating microglial/macrophage M1/M2 polarization and neuroinflammation following TBI. Methods The controlled cortical impact (CCI) mouse model was employed. Mer siRNA was intracerebroventricularly administered, and recombinant protein S (PS) was intravenously applied for intervention. The neurobehavioral assessments, RT-PCR, Western blot, magnetic-activated cell sorting, immunohistochemistry and confocal microscopy analysis, Nissl and Fluoro-Jade B staining, brain water content measurement, and contusion volume assessment were performed. Results Mer is upregulated and regulates microglial/macrophage M1/M2 polarization and neuroinflammation in the acute stage of TBI. Mechanistically, Mer activates the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition of Mer markedly decreases microglial/macrophage M2-like polarization while increases M1-like polarization, which exacerbates the secondary brain damage and sensorimotor deficits after TBI. Recombinant PS exerts beneficial effects in TBI mice through Mer activation. Conclusions Mer is an important regulator of microglial/macrophage M1/M2 polarization and neuroinflammation, and may be considered as a potential target for therapeutic intervention in TBI.

Background Intracerebral hemorrhage (ICH) can induce excessive accumulation of reactive oxygen species (ROS) that may subsequently cause severe white matter injury. The process of oligodendrocyte progenitor cell (OPC) differentiation is orchestrated by microglia and astrocytes, and ROS also drives the activation of microglia and astrocytes. In light of the potent ROS scavenging capacity of ceria nanoparticles (CeNP), we aimed to investigate whether treatment with CeNP ameliorates white matter injury by modulating ROS-induced microglial polarization and astrocyte alteration. Methods ICH was induced in vivo by collagenase VII injection. Mice were administered with PLX3397 for depleting microglia. Primary microglia and astrocytes were used for in vitro experiments. Transmission electron microscopy analysis and immunostaining were performed to verify the positive effects of CeNP in remyelination and OPC differentiation. Flow cytometry, real-time polymerase chain reaction, immunofluorescence and western blotting were used to detect microglia polarization, astrocyte alteration, and the underlying molecular mechanisms. Results CeNP treatment strongly inhibited ROS-induced NF-κB p65 translocation in both microglia and astrocytes, and significantly decreased the expression of M1 microglia and A1 astrocyte. Furthermore, we found that CeNP treatment promoted remyelination and OPC differentiation after ICH, and such effects were alleviated after microglial depletion. Interestingly, we also found that the number of mature oligodendrocytes was moderately increased in ICH + CeNP + PLX3397-treated mice compared to the ICH + vehicle + PLX3397 group. Therefore, astrocytes might participate in the pathophysiological process. The subsequent phagocytosis assay indicated that A1 astrocyte highly expressed C3, which could bind with microglia C3aR and hinder microglial engulfment of myelin debris. This result further replenished the feedback mechanism from astrocytes to microglia. Conclusion The present study reveals a new mechanism in white matter injury after ICH: ICH induces M1 microglia and A1 astrocyte through ROS-induced NF-κB p65 translocation that hinders OPC maturation. Subsequently, A1 astrocytes inhibit microglial phagocytosis of myelin debris via an astrocytic C3-microglial C3aR axis. Polyethylene glycol-CeNP treatment inhibits this pathological process and ultimately promotes remyelination. Such findings enlighten us that astrocytes and microglia should be regarded as a functional unit in future works.

Background Early severe cerebral edema and chronic hydrocephalus are the primary cause of poor prognosis in patients with subarachnoid hemorrhage (SAH). This study investigated the role of cerebrospinal fluid (CSF) inflammatory cytokines and coagulation factors in the development of severe cerebral edema and chronic hydrocephalus in patients with SAH. Methods Patients with SAH enrolled in this study were categorized into mild and severe cerebral edema groups based on the Subarachnoid Hemorrhage Early Brain Edema Score at admission. During long-term follow-up, patients were further classified into hydrocephalus and non-hydrocephalus groups. CSF samples were collected within 48 h post-SAH, and levels of inflammatory cytokines and coagulation factors were measured. Univariate and multivariate logistic regression analyses were performed to identify independent factors associated with severe cerebral edema and chronic hydrocephalus. The correlation between inflammatory cytokines and coagulation factors was further investigated and validated in a mouse model of SAH. Results Seventy-two patients were enrolled in the study. Factors from the extrinsic coagulation pathway and inflammatory cytokines were associated with both severe cerebral edema and chronic hydrocephalus. Coagulation products thrombin-antithrombin complexes (TAT) and fibrin, as well as inflammatory cytokines IL-1β, IL-2, IL-5, IL-7, and IL-4, were independently associated with severe cerebral edema. Additionally, Factor VII, fibrin, IL-2, IL-5, IL-12, TNF-α, and CCL-4 were independently associated with chronic hydrocephalus. A positive correlation between extrinsic coagulation factors and inflammatory cytokines was observed. In the SAH mouse model, tissue plasminogen activator was shown to alleviate neuroinflammation and cerebral edema, potentially by restoring glymphatic-meningeal lymphatic function. Conclusions Elevated levels of inflammatory cytokines and extrinsic coagulation pathway factors in the CSF are associated with the development of early severe cerebral edema and chronic hydrocephalus following SAH. These factors are interrelated and may contribute to post-SAH glymphatic-meningeal lymphatic dysfunction.

Hemorrhagic stroke is a life-threatening neurological disease characterized by high mortality and morbidity. Various pathophysiological responses are initiated after blood enters the interstitial space of the brain, compressing the brain tissue and thus causing cell death. Recently, three new programmed cell deaths (PCDs), necroptosis, pyroptosis, and ferroptosis, were also found to be important contributors in the pathophysiology of hemorrhagic stroke. Additionally, blood-brain barrier (BBB) dysfunction plays a crucial role in the pathophysiology of hemorrhagic stroke. The primary insult following BBB dysfunction may disrupt the tight junctions (TJs), transporters, transcytosis, and leukocyte adhesion molecule expression, which may lead to brain edema, ionic homeostasis disruption, altered signaling, and immune infiltration, consequently causing neuronal cell death. This review article summarizes recent advances in our knowledge of the mechanisms regarding these new PCDs and reviews their contributions in hemorrhagic stroke and potential crosstalk in BBB dysfunction. Numerous studies revealed that necroptosis, pyroptosis, and ferroptosis participate in cell death after subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). Endothelial dysfunction caused by these three PCDs may be the critical factor during BBB damage. Also, several signaling pathways were involved in PCDs and BBB dysfunction. These new PCDs (necroptosis, pyroptosis, ferroptosis), as well as BBB dysfunction, each play a critical role after hemorrhagic stroke. A better understanding of the interrelationship among them might provide us with better therapeutic targets for the treatment of hemorrhagic stroke.

Background Germinal matrix hemorrhage (GMH) is defined by the rupture of immature blood vessels in the germinal matrix, where subsequent hemorrhage enters the subependymal zone and the cerebral lateral ventricles. The consequent blood clot has been identified as the causative factor of secondary brain injury, which triggers a series of complex parallel and sequential harmful mechanisms, including neuroinflammation. The orphan G-protein-coupled receptor 40 (GPR40), a free fatty acid (FFA) receptor 1, has been shown to exert anti-inflammatory effects when activated and improved outcomes in animal models of stroke. We aimed to investigate the anti-inflammatory effects of GPR40 and its underlying mechanisms after GMH. Methods GMH model was induced in 7-day-old rat pups by an intraparenchymal injection of bacterial collagenase. GPR40 agonist, GW9508, was administered intranasally 1 h, 25 h, and 49 h after GMH induction. CRISPR targeting GPR40, PAK4, and KDM6B were administered through intracerebroventricular injection 48 h before GMH induction. Neurologic scores, microglia polarization, and brain morphology were evaluated by negative geotaxis, right reflex, rotarod test, foot fault test, Morris water maze, immunofluorescence staining, Western blots, and nissl staining respectfully. Results The results demonstrated that GW9508 improved neurological and morphological outcomes after GMH in the short (24 h, 48 h, 72h) and long-term (days 21–27). However, the neuroprotective effects of treatment were abolished by GW1100, a selective GPR40 antagonist. GW9508 treatment increased populations of M2 microglia and decreased M1 microglia in periventricular areas 24 h after GMH induction. GW9508 upregulated the phosphorylation of PAK4, CREB, and protein level of KDM6B, CD206, IL-10, which was also met with the downregulation of inflammatory markers IL-1β and TNF-α. The mechanism study demonstrated that the knockdown of GPR40, PAK4, and KDM6B reversed the neuroprotective effects brought on by GW9508. This evidence suggests that GPR40/PAK4/CREB/KDM6B signaling pathway in microglia plays a role in the attenuation of neuroinflammation after GMH. Conclusions In conclusion, the present study demonstrates that the activation of GPR40 attenuated GMH-induced neuroinflammation through the activation of the PAK4/CREB/KDM6B signaling pathway, and M2 microglia may be a major mediator of this effect. Thus, GPR40 may serve as a potential target in the reduction of the inflammatory response following GMH, thereby improving neurological outcomes in the short- and long-term.

Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short- and long-term neurological benefits by preserving the function of the blood–brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC–cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH.

Past studies revealed the prognosis differed between aneurysmal subarachnoid hemorrhage (aSAH) patients with surgical clipping and endovascular coiling. We retrospectively reviewed aSAH patients in our institution to investigate the effectiveness of grading scores between two groups. In the surgical clipping group (n = 349), VASOGRADE had a favorable performance for predicting delayed cerebral ischemia (DCI) (area under curve (AUC) > 0.750), and had better results than clinical (World Federation of Neurosurgical Societies (WFNS), Hunt & Hess (HH) and radiological scores (modified Fisher Scale (mFS), Subarachnoid Hemorrhage Early Brain Edema Score) ( P  < 0.05). Clinical and combined scores (VASOGRADE, HAIR) had favorable performance for predicting poor outcome (AUC > 0.750), and had better results than radiological scores ( P  < 0.05). In the coiling group (n = 320), none of the grading scores demonstrated favorable predictive accuracy for DCI (AUC < 0.750). Only WFNS and VASOGRADE had AUC > 0.700, with better performance than mFS ( P  < 0.05). The clinical and combined scores showed favorable performance for predicting a poor outcome (AUC > 0.750), and were better than the radiological scores ( P  < 0.05). Radiological scores appeared inferior to the clinical and combined scores in clipping and coiling groups. VASOGRADE can be an effective grading score in patients with clipping or coiling for predicting DCI and poor outcome.

Background Meningeal lymphatic vessels (mLVs) play a critical role in clearing erythrocytes from the subarachnoid space and immune cells from the brain parenchyma following subarachnoid hemorrhage (SAH). However, the drainage function of mLVs is impaired during the acute stage after SAH and gradually recovers in the subacute phase. We aimed to investigate the meningeal transcriptional response post-SAH and elucidate the dynamic influence of meningeal microenvironment on meningeal lymphatic function. Methods We employed bioinformatics analysis of single-cell RNA sequencing and spatial transcriptomics to characterize the spatiotemporal dynamic changes in the early meningeal microenvironment post-SAH. In a mouse model of SAH, the early dynamic changes of the meningeal immune cells and the potential growth factor that promoted the early repair of the mLVs were further investigated and validated. Results During the acute phase, myeloid cells early infiltrated the meninges and triggered inflammatory responses. In the subacute phase, the fibroblast population expanded significantly, contributing to tissue remodeling. The interplay between immune cells and fibroblasts regulated cell migration and phenotypic transition, potentially affecting the function of mLVs. Notably, placental growth factor (PGF) emerged as the most prominent ligand within the VEGF signaling pathway received by meningeal lymphatic endothelial cells (mLECs) post-SAH. This signaling event was associated with the early recovery of mLVs after acute immune responses. Conclusions Our study revealed a spatiotemporal transformation of the meningeal microenvironment from an “inflammatory response” phase to a “tissue remodeling” phase following SAH. Monocyte-derived macrophages and self-recruiting neutrophils contributed to impairment of mLVs in the acute stage, while PGF might serve as a key factor promoting early meningeal lymphatic function repair following the inflammatory response. These findings provided novel insights into the cellular dynamics underlying mLVs dysfunction and recovery post-SAH. Graphical Abstract

The role of glial scar after intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar. We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation. Spatial transcriptomics (ST) analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods. During the early stage, sustained microglial depletion induced disorganized astrocytic scar, enhanced neutrophil infiltration, and impaired tissue repair. ST analysis indicated that microglia-derived insulin like growth factor 1 (IGF1) modulated astrocytic scar formation via mechanistic target of rapamycin (mTOR) signaling activation. Moreover, repopulating microglia (RM) more strongly activated mTOR signaling, facilitating a more protective scar formation. The combination of IGF1 and osteopontin (OPN) was necessary and sufficient for RM function, rather than IGF1 or OPN alone. At the chronic stage of ICH, the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this. The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH. Inversely, early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy. This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes, and develop elaborate treatment strategies at precise time points after ICH. [Display omitted] •Sustained microglial depletion induce disorganized astrocytic scar after ICH.•Microglia-derived IGF1 modulates glial scar formation via mTOR signaling activation.•Repopulating microglia facilitate tissue repair via the combination of IGF1 and OPN.•The glial scar transforms from protection into destruction at chronic stage of ICH.•The elaborate treatment strategies at precise time points should be implemented after ICH.