Qinghua Wang

Background: Decompressive craniectomy has been widely evaluated across heterogeneous brain injury phenotypes, but its effect in patients with acute epidural haematoma (AEDH) complicated by herniation remains unclear. We assessed whether decompressive craniectomy improves clinically important outcomes in patients with massive AEDH and tentorial herniation. Methods: The Prospective Randomised Evaluation of Decompressive Ipsilateral Craniectomy for Traumatic Acute Epidural Haematoma (PREDICT-AEDH) was a nationwide, multicentre, open-label, parallel-group randomised controlled trial conducted at 28 hospitals in China. Adults aged 18–65 years with CT-confirmed massive AEDH and tentorial herniation within 12 h of injury were randomly assigned (1:1) to primary decompressive craniectomy or standard craniotomy with bone-flap replacement. The primary outcome was functional status at 6 months, assessed using the Glasgow Outcome Scale–Extended (GOSE) and analysed with a proportional-odds model. Analyses were performed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (NCT04261673) and is complete. Findings: Between Sept 2020 and March 2025, 120 patients were randomly assigned to decompressive craniectomy (n=58) or craniotomy (n=62). At 6 months, a favourable functional outcome (GOSE ≥5) occurred in 46 (79·31%) patients in the decompressive craniectomy group and 52 (83·87%) in the craniotomy group (odds ratio 0·73, 95% CI 0·26–2·07; p=0·638). Ordinal analysis of GOSE showed no significant difference between groups (common odds ratio 0·79, 95% CI 0·41–1·58; p=0·514). Thirty-day mortality, postoperative cerebral infarction, and early repeat cranial surgery were similar between groups. Delayed intracranial haematoma occurred more frequently after decompressive craniectomy than after craniotomy (21 [36·20%] vs 8 [12·90%]; OR 3·79, 95% CI 1·43–11·00; p=0·004). Interpretation: In patients with massive AEDH and tentorial herniation, decompressive craniectomy did not improve 6-month functional outcomes compared with standard craniotomy and increased the risk of delayed intracranial haematoma and subsequent surgery. These findings do not support routine prophylactic decompressive craniectomy in this population.

Intracerebral hemorrhage (ICH) is a devastating disease that disrupts the blood–brain barrier (BBB), triggers inflammation, and leads to subsequent neurological deficits. Although the CXC chemokine receptor 3 (CXCR3) and its ligand CXCL10 are implicated in regulating inflammation, the specific role and mechanism of CXCR3 in ICH-induced BBB disruption remain unclear; furthermore, the involvement of the cGAS/AIM2 signaling pathway in endothelial pyroptosis after ICH needs further investigation. This study elucidates that activation of the CXCR3/CXCL10 axis exacerbates disruption of BBB integrity via the cGAS/AIM2 pathway following ICH. Utilizing a type IV collagenase-induced ICH model, we evaluated the therapeutic efficacy of the CXCR3 inhibitor AMG487. Results demonstrated that ICH induced the upregulation of CXCR3 and CXCL10, peaking at 24 h; immunofluorescence co-localization indicated CXCR3 was primarily localized to endothelial cells, while CXCL10 originated mainly from endothelial cells and astrocytes. AMG487 treatment improved neurological deficits and attenuated BBB disruption after ICH. Furthermore, exogenous CXCL10 activating CXCR3 upregulated the expression of cGAS/STING and pyroptosis-related proteins in vivo and vitro ICH models. However, inhibiting CXCR3 reversed the poor effects induced by CXCL10. Inhibition of the cGAS/AIM2 signaling pathway using A151 effectively reduced vascular endothelial pyroptosis and BBB disruption. In a co-culture model of endothelial cells and astrocytes, depleting CXCL10 downregulated the expression of cGAS, STING, AIM2, and pyroptosis-related proteins and alleviated endothelial pyroptosis. This study demonstrates that inhibition CXCR3 preserves BBB integrity and improves neurological deficits after ICH by suppressing endothelial pyroptosis via the cGAS/AIM2 signaling pathway. These findings provide novel insights into ICH pathogenesis, proposing CXCR3 as a potential target for BBB disruption and AMG487 as a promising therapeutic strategy for ICH patients.

Background: Neuroinflammatory reactions are crucial factors in secondary brain damage following intracerebral hemorrhage (ICH). Although previous studies have shown that IRAK3 is involved in immune responses, the potential effects of IRAK3 on ICH remain unclear. Methods: Collagenase IV–induced ICH mouse model. Western blotting was used to determine the expression of IRAK3 at different time points following ICH. Immunofluorescence was used to investigate the cellular localization of IRAK3. The ICH model was treated with recombinant human IRAK3 (rh-IRAK3) or IRAK3 siRNA via an intracerebroventricular injection. The effect of IRAK3 on ICH mice was assessed by Western blotting and short-term and long-term neurological function evaluation. RNA-seq was performed to explore the mechanism by which IRAK3 promotes inflammation after ICH. The mechanisms of IRAK3 and neuroinflammation will be further investigated by Western blotting, qRT-PCR and immunofluorescence. Recombinant IL-17A was used to investigate the connection between IRAK3 and the NF-κB/IL-17A signaling pathway in vivo and in vitro experiments. Results: The expression of IRAK3 increased, peaking at 24 h, followed by a subsequent decrease after ICH. IRAK3 is mainly expressed in the microglia. RNA-seq analysis revealed 1,797 differentially expressed genes around the perihematomal brain tissue after IRAK3 siRNA treatment, with multiple inflammatory pathways being downregulated. Rh-IRAK3 treatment resulted in upregulation of the levels of inflammatory cytokines around the perihematomal tissue and exacerbated neurological function deficits. Furthermore, IRAK3 siRNA treatment markedly decreased the expression of inflammatory cytokines and microglial activation via the NF-κB/IL-17A signaling pathway. Recombinant IL-17A exacerbated the inflammatory response in vivo and in vitro; however, IRAK3 knockdown reversed this process. Conclusion: IRAK3 aggravates neuroinflammation by activating the NF-κB/IL-17A signaling pathway, thereby exacerbating neurological deficits following ICH. Therefore, inhibition IRAK3 may be a promising approach for treating ICH.

Neuroinflammation and microglia polarization play pivotal roles in brain injury induced by intracerebral hemorrhage (ICH). Despite the well-established involvement of CXC motif chemokine ligand 16 (CXCL16) in regulating inflammatory responses across various diseases, its specific functions in the context of neuroinflammation and microglial polarization following ICH remain elusive. In this study, we investigated the impact of CXCL16 on neuroinflammation and microglia polarization using both mouse and cell models. Our findings revealed elevated CXCL16 expression in mice following ICH and in BV2 cells after lipopolysaccharide (LPS) stimulation. Specific silencing of CXCL16 using siRNA led to a reduction in the expression of neuroinflammatory factors, including IL-1β and IL-6, as well as decreased expression of the M1 microglia marker iNOS. Simultaneously, it enhanced the expression of anti-inflammatory factors such as IL-10 and the M2 microglia marker Arg-1. These results were consistent across both mouse and cell models. Intriguingly, co-administration of the PI3K-specific agonist 740 Y-P with siRNA in LPS-stimulated cells reversed the effects of siRNA. In conclusion, silencing CXCL16 can positively alleviate neuroinflammation and M1 microglial polarization in BV2 inflammation models and ICH mice. Furthermore, in BV2 cells, this beneficial effect is mediated through the PI3K/Akt pathway. Inhibition of CXCL16 could be a novel approach for treating and diagnosing cerebral hemorrhage.

Pro-inflammatory signals generated after intracerebral hemorrhage (ICH) trigger a form of regulated cell death known as pyroptosis in microglia. White matter injury (WMI) refers to the condition where the white matter area of the brain suffers from mechanical, ischemic, metabolic, or inflammatory damage. Although the p2Y purinoceptor 6 (P2Y6R) plays a significant role in the control of inflammatory reactions in central nervous system diseases, its roles in the development of microglial pyroptosis and WMI following ICH remain unclear. In this study, we sought to clarify the role of P2Y6R in microglial pyroptosis and WMI by using an experimental mouse model of ICH. Type IV collagenase was injected into male C57BL/6 mice to induce ICH. Mice were then treated with MRS2578 and LY294002 to inhibit P2Y6R and phosphatidylinositol 3-kinase (PI3K), respectively. Bio-conductivity analysis was performed to examine PI3K/AKT pathway involvement in microglial pyroptosis. Quantitative Real-Time PCR, immunofluorescence staining, and western blot were conducted to examine microglial pyroptosis and WMI following ICH. A modified Garcia test, corner turning test, and forelimb placement test were used to assess neurobehavior. Hematoxylin-eosin staining (HE) was performed to detect cells damage around hematoma. Increases in the expression of P2Y6R, NLRP3, ASC, Caspase-1, and GSDMD were observed after ICH. P2Y6R was only expressed on microglia. MRS2578, a specific inhibitor of P2Y6R, attenuated short-term neurobehavioral deficits, brain edema and hematoma volume while improving both microglial pyroptosis and WMI. These changes were accompanied by decreases in pyroptosis-related proteins and pro-inflammatory cytokines both in vivo and vitro. Bioinformatic analysis revealed an association between the PI3K/AKT pathway and P2Y6R-mediated microglial pyroptosis. The effects of MRS2578 were partially reversed by treatment with LY294002, a specific PI3K inhibitor. P2Y6R inhibition alleviates microglial pyroptosis and WMI and ameliorates neurological deficits through the PI3K/AKT pathway after ICH. Consequently, targeting P2Y6R might be a promising approach for ICH treatment.

Background Pro-inflammatory signals generated after intracerebral hemorrhage (ICH) trigger a form of regulated cell death known as pyroptosis in microglia. Although the p2Y purinoceptor 6 (P2RY6) plays a significant role in control of inflammatory reactions in central nervous system diseases, its roles in the development of neuroinflammation and microglial pyroptosis following ICH remain unclear. Methods Type IV collagenase was injected to induce ICH. Mice were then treated with MRS2578 and LY294002 to inhibit P2RY6 and phosphatidylinositol 3-kinase (PI3K), respectively. Bio-conductivity analysis was performed to examine PI3K/AKT pathway involvement. Immunostaining and quantitative polymerase chain reaction (qPCR) analyses were conducted to examine pyroptosis following P2RY6 inhibitor treatment. Western blot and immunostaining were performed to clarify the specific mechanisms underlying microglia pyroptosis and white matter injury (WMI). A modified Garcia test, corner turning test, and forelimb placement test were used to assess neurobehavioral function. Results Increases in the expression of P2RY6 and pyroptosis-related proteins were observed after ICH, peaking 24 h post ICH. P2RY6 was only expressed on microglia. Administration of MRS2578, a specific inhibitor of P2RY6, attenuated short-term neurobehavioral deficits and WMI while decreasing both microglia pyroptosis and cerebral edema. These changes were attended by decreases in pyroptosis-relatived proteins and pro-inflammatory cytokines. Bioinformatic analysis revealed an association between the PI3K/AKT pathway and P2RY6-mediated neuroinflammation. The effects of MRS2578 were partially reversed by treatment with LY294002, a specific PI3K inhibitor. Conclusion P2RY6 activation induces microglial pyroptosis, deficits in neurological function and WMI, partially via the P2RY6/PI3K/AKT/NLRP3 pathway. Consequently, targeting P2RY6 might be a promising approach to the therapy of ICH.

Background: Neuroinflammation plays an important role following intracerebral hemorrhage (ICH). NLRP3 inflammasome-mediated pyroptosis contributes to the mechanism of neuroinflammation. It has been reported that dendritic cell-associated C-type lectin-1 (Dectin-1) activation triggers inflammation in neurological diseases. However, the role of Dectin-1 on NLRP3 inflammasome-mediated pyroptosis after ICH remains unclear. Here, we aimed to explore the effect of Dectin-1 on NLRP3 inflammasome-mediated pyroptosis and neuroinflammation after ICH. Methods: Adult male C57BL/6 mice were used to establish the ICH model. Laminarin, an inhibitor of Dectin-1, was administered for intervention. Expression of Dectin-1 was evaluated by Western blot and immunofluorescence. Brain water content and neurobehavioral function were tested to assess brain edema and neurological performance. Western blot was conducted to evaluate the level of GSDMD-N. ELISA kits were used to measure the levels of IL-1β and IL-18. qRT–PCR and Western blot were performed to evaluate the expressions of NLRP3 inflammasome, IL-1β, and IL-18. Results: The expression of Dectin-1 increased following ICH, and Dectin-1 was expressed on microglia. In addition, inhibition of Dectin-1 by laminarin decreased brain edema and neurological impairment after ICH. Moreover, inhibition of Dectin-1 decreased the expression of pyroptosis-related protein, GSDMD-N, and inflammatory cytokines (IL-1β and IL-18). Mechanistically, Dectin-1 blockade inhibits NLRP3 inflammasome activation, thereby alleviating neuroinflammatory injury by attenuating NLRP3 inflammasome-mediated pyroptosis both in vivo and in vitro. Conclusion: Our study indicates that the inhibition of Dectin-1 alleviates neuroinflammation by attenuating NLRP3 inflammasome-mediated pyroptosis after ICH.

Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke; there is still a lack of effective treatment. Microglia are a major component of the innate immune system, and they respond to acute brain injury by activating and forming classic M1-like (pro-inflammatory) or alternative M2-like (anti-inflammatory) phenotype. The existence of the polarization indicates that the role of microglia in disease’s progression and recovery after ICH is still unclear, perhaps involving microglial secretion of anti-inflammatory or pro-inflammatory cytokines and chemokines. The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is considered to be the main participant in neuroinflammation. Recent evidence has shown that NLRP3 inflammasome can be activated after ICH, resulting in inflammatory cascade reactions and aggravating brain injury. Furthermore, previous studies have reported that NLRP3 inflammasome is mainly present in microglia, so we speculate that its activation may be strongly associated with microglial polarization. Many scholars have investigated the role of brain injury caused by NLRP3 inflammasome after ICH, but the precise operating mechanisms remain uncertain. This review summarized the activation mechanism of NLRP3 inflammasome after ICH and the possible mechanism of NLRP3 inflammasome promoting neuroinflammation and aggravating nerve injury and discussed the relevant potential therapeutic targets.