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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immune-surveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

Cytosolic double‐stranded DNA (dsDNA) is a danger signal that is tightly monitored and sensed by nucleic acid‐sensing pattern recognition receptors. We study the inflammatory cascade on dsDNA recognition and investigate the neuroprotective effect of cyclic GMP‐AMP (cGAMP) synthase (cGAS) antagonist A151 and its mechanisms of neuroprotection in a mouse model of experimental stroke. Here, we found that cerebral ischemia promoted the release of dsDNA into the cytosol, where it initiated inflammatory responses by activating the cGAS. A151 effectively reduced the expression of cGAS, absent in melanoma 2 (AIM2) inflammasome, and pyroptosis‐related molecules, including caspase‐1, gasdermin D, IL‐1β, and IL‐18. Furthermore, mice treated with A151 showed a dampened immune response to stroke, with reduced counts of neutrophils, microglia, and microglial production of IL‐6 and TNF‐α after MCAO. Moreover, A151 administration significantly reduced infarct volume, attenuated neurodeficits, and diminished cell death. Notably, the protective effect of A151 was blocked in a microglia‐specific cGAS knockout mouse. These findings offer unique perspectives on stroke pathogenesis and indicate that inhibition of cGAS could attenuate brain inflammatory burden, representing a potential therapeutic opportunity for stroke. Synopsis Inflammation is involved in the progression of ischemic brain injury. This study focuses on the inflammatory cascade on double‐strand DNA (dsDNA) recognition and highlights the possibility of inhibiting dsDNA‐sensing cyclic GMP‐AMP synthase (cGAS) for treatment of ischemic stroke. The release of dsDNA from necrotic tissue during brain infarction triggers an innate inflammatory cascade. A synthetic oligonucleotide A151 that antagonizes cGAS regulates the microglial immune response and pyroptosis after ischemic stroke. Inhibition of cGAS leads to a decline in neutrophil infiltration into the brain. Suppression of the dsDNA‐sensing cGAS pathway reduces ischemic brain injury via mitigating neuroinflammation. Graphical Abstract Inflammation is involved in the progression of ischemic brain injury. This study focuses on the inflammatory cascade on double‐strand DNA (dsDNA) recognition and highlights the possibility of inhibiting dsDNA‐sensing cyclic GMP‐AMP synthase (cGAS) for treatment of ischemic stroke.

Limited knowledge exists regarding the ramifications of climate warming on death burden from neurodegenerative diseases. Here, we conducted a nationwide, individual-level, case-crossover study between 2013 and 2019 to investigate the effects of non-optimal temperatures on various neurodegenerative diseases and to predict the potential death burden under different climate change scenarios. Our findings reveal that both low and high temperatures are linked to increased risks of neurodegenerative diseases death. We project that heat-related neurodegenerative disease deaths would increase, while cold-related deaths would decrease. This is characterized by a steeper slope in the high-emission scenario, but a less pronounced trend in the scenarios involving mitigation strategies. Furthermore, we predict that the net changes in attributable death would increase after the mid-21st century, especially under the unrestricted-emission scenario. These results highlight the urgent need for effective climate and public health policies to address the growing challenges of neurodegenerative diseases associated with global warming. Examining non-optimal temperatures’ influence on neurodegenerative diseases amid climate warming is vital for public health. Here, the authors project a notable net increase of death burden from neurodegenerative diseases after the mid-21st century.

Background Neuroinflammation and immune responses occurring minutes to hours after stroke are associated with brain injury after acute ischemic stroke (AIS). PPARγ coactivator-1α (PGC-1α), as a master coregulator of gene expression in mitochondrial biogenesis, was found to be transiently upregulated in microglia after AIS. However, the role of microglial PGC-1α in poststroke immune modulation remains unknown. Methods PGC-1α expression in microglia from human and mouse brain samples following ischemic stroke was first determined. Subsequently, we employed transgenic mice with microglia-specific overexpression of PGC-1α for middle cerebral artery occlusion (MCAO). The morphology and gene expression profile of microglia with PGC-1α overexpression were evaluated. Downstream inflammatory cytokine production and NLRP3 activation were also determined. ChIP-Seq analysis was performed to detect PGC-1α-binding sites in microglia. Autophagic and mitophagic activity was further monitored by immunofluorescence staining. Unc-51-like autophagy activating kinase 1 (ULK1) expression was evaluated under the PGC-1α interaction with ERRα. Finally, pharmacological inhibition and genomic knockdown of ULK1 were performed to estimate the role of ULK1 in mediating mitophagic activity after ischemic stroke. Results PGC-1α expression was shortly increased after ischemic stroke, not only in human brain samples but also in mouse brain samples. Microglia-specific PGC-1α overexpressing mice exhibited significantly decreased neurologic deficits after ischemic injury, with reduced NLRP3 activation and proinflammatory cytokine production. ChIP-Seq analysis and KEGG pathway analysis revealed that mitophagy was significantly enhanced. PGC-1α significantly promoted autophagic flux and induced autolysosome formation. More specifically, the autophagic clearance of mitochondria was enhanced by PGC-1α regulation, indicating the important role of mitophagy. Pharmacological inhibition or knockdown of ULK1 expression impaired autophagic/mitophagic activity, thus abolishing the neuroprotective effects of PGC-1α. Conclusions Mechanistically, in AIS, PGC-1α promotes autophagy and mitophagy through ULK1 and reduces NLRP3 activation. Our findings indicate that microglial PGC-1α may be a promising therapeutic target for AIS.

Background Guillain–Barré syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. Dimethyl fumarate (DMF), a fumaric acid ester, exhibits various biological activities, including multiple immunomodulatory and neuroprotective effects. However, the potential mechanism underlying the effect of DMF in GBS animal model experimental autoimmune neuritis (EAN) is unclear. Methods Using EAN, an established GBS model, we investigated the effect of DMF by assessing clinical score, histological staining and electrophysiological studies. Then, we further explored the potential mechanism by Western blot analysis, flow cytometry, fluorescence immunohistochemistry, PCR, and ELISA analysis. The Mann–Whitney U test was used to compare differences between control group and treatment groups where appropriate. Results DMF treatment reduced the neurological deficits by ameliorating inflammatory cell infiltration and demyelination of sciatic nerves. In addition, DMF treatment decreased the level of pro-inflammatory M1 macrophages while increasing the number of anti-inflammatory M2 macrophages in the spleens and sciatic nerves of EAN rats. In RAW 264.7, a shift in macrophage polarization from M1 to M2 phenotype was demonstrated to be depended on DMF application. In sciatic nerves, DMF treatment elevated the level of the antioxidant transcription factor nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and its target gene hemoxygenase-1 (HO-1) which could facilitate macrophage polarization toward M2 type. Moreover, DMF improved the inflammatory milieu in spleens of EAN rats, characterized by downregulation of messenger RNA (mRNA) of IFN-γ, TNF-α, IL-6, and IL-17 and upregulation of mRNA level of IL-4 and IL-10. Conclusions Taken together, our data demonstrate that DMF can effectively suppress EAN, and the mechanism involves altering the balance of M1/M2 macrophages and attenuating inflammation.

Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15–expressing transgenic mouse (GFAP–IL-15tg) line and found enlarged brain infarcts, exacerbated neurodeficits after the induction of brain ischemia. In addition, knockdown of IL-15 in astrocytes attenuated ischemic brain injury. Interestingly, the accumulation of CD8⁺ T and natural killer (NK) cells was augmented in these GFAP–IL-15tg mice after brain ischemia. Of note, depletion of CD8⁺ T or NK cells attenuated ischemic brain injury in GFAP–IL-15tg mice. Furthermore, knockdown of the IL-15 receptor α or blockade of cell-to-cell contact diminished the activation and effector function of CD8⁺ T and NK cells in GFAP–IL-15tg mice, suggesting that astrocytic IL-15 is delivered in trans to target cells. Collectively, these findings indicate that astrocytic IL-15 could aggravate postischemic brain damage via propagation of CD8⁺ T and NK cell-mediated immunity.

Vitamin D deficiency is associated with worse clinical outcomes after ischemic stroke; nevertheless, the pathophysiological mechanisms remain largely unexplored. In this study, we characterized the molecular mechanisms of how vitamin D signaling modulated stroke progression in male mouse ischemia–reperfusion stroke models. We found that vitamin D receptor (VDR) exhibited a predominant upregulation in peri-infarct microglia/macrophages following cerebral ischemia. Conditional Vdr inactivation in microglia/macrophages markedly augmented infarct volumes and neurological deficits. VDR-deficient microglia/macrophages exhibited a more primed proinflammatory phenotype with substantial secretion of TNF-α and IFN-γ. These inflammatory cytokines further enhanced CXCL10 release from endothelial cells and blood–brain barrier disruption, and ultimately infiltration of peripheral T lymphocytes. Notably, blocking TNF-α and IFN-γ significantly ameliorated stroke phenotypes in Vdr conditional knockout mice. Collectively, VDR signaling in microglia/macrophages plays a crucial role in restraining ischemia-elicited neuroinflammation and stroke progression. Our findings delineate a novel mechanism underlying the association between vitamin D deficiency and poor stroke outcomes, and underline the significance of maintaining a functional vitamin D signaling in the management of acute ischemic stroke.

Peripheral lymphocytes entering brain ischemic regions orchestrate inflammatory responses, catalyze tissue death, and worsen clinical outcomes of acute ischemic stroke (AIS) in preclinical studies. However, it is not known whether modulating brain inflammation can impact the outcome of patients with AIS. In this open-label, evaluator-blinded, parallel-group clinical pilot trial, we recruited 22 patients matched for clinical and MRI characteristics, with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h, who then received standard management alone (controls) or standard management plus fingolimod (FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive days. Compared with the 11 control patients, the 11 fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and better recovery of neurological functions. This difference was most profound in the first week when reduction of National Institutes of Health Stroke Scale was 4 vs. −1, respectively ( P = 0.0001). Neurological rehabilitation was faster in the fingolimod-treated group. Enlargement of lesion size was more restrained between baseline and day 7 than in controls (9 vs. 27 mL, P = 0.0494). Furthermore, rT1%, an indicator of microvascular permeability, was lower in the fingolimod-treated group at 7 d (20.5 vs. 11.0; P = 0.005). No drug-related serious events occurred. We conclude that in patients with acute and anterior cerebral circulation occlusion stroke, oral fingolimod within 72 h of disease onset was safe, limited secondary tissue injury from baseline to 7 d, decreased microvascular permeability, attenuated neurological deficits, and promoted recovery. Significance In patients with acute ischemic stroke (AIS), the abrupt and massive influx of lymphocytes from the periphery to the ischemic region orchestrates focal inflammatory responses, catalyzes tissue death, and worsens clinical outcomes. In this early phase clinical study, we reduced lymphocyte migration to the brain during the first 72 h of AIS via oral administration of three doses of fingolimod. This administration led to a significant reduction of secondary lesion enlargement, microvascular permeability, and better clinical outcomes during the acute phase and 3-mo follow-up visit. This study will provoke new investigations on the efficacy of modulation of brain inflammation in AIS.

Inflammation and oxidative stress play an important part in the pathogenesis of focal cerebral ischemia/reperfusion (I/R) injury, resulting in neuronal death. The signaling pathways involved and the underlying mechanisms of these events are not fully understood. Chrysin, which is a naturally occurring flavonoid, exhibits various biological activities. In this study, we investigated the neuroprotective properties of chrysin in a mouse model of middle cerebral artery occlusion (MCAO). To this end, male C57/BL6 mice were pretreated with chrysin once a day for seven days and were then subjected to 1 h of middle cerebral artery occlusion followed by reperfusion for 24 h. Our data show that chrysin successfully decreased neurological deficit scores and infarct volumes, compared with the vehicle group. The increases in glial cell numbers and proinflammatory cytokine secretion usually caused by ischemia/reperfusion were significantly ameliorated by chrysin pretreatment. Moreover, chrysin also inhibited the MCAO-induced up-regulation of nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), compared with the vehicle. These results suggest that chrysin could be a potential prophylactic agent for cerebral ischemia/reperfusion (I/R) injury mediated by its anti-inflammatory and anti-oxidative effects.

The brain-computer interface (BCI) is a technology that involves direct communication with parts of the brain and has evolved rapidly in recent years; it has begun to be used in clinical practice, such as for patient rehabilitation. Patient electroencephalography (EEG) datasets are critical for algorithm optimization and clinical applications of BCIs but are rare at present. We collected data from 50 acute stroke patients with wireless portable saline EEG devices during the performance of two tasks: 1) imagining right-handed movements and 2) imagining left-handed movements. The dataset consists of four types of data: 1) the motor imagery instructions, 2) raw recording data, 3) pre-processed data after removing artefacts and other manipulations, and 4) patient characteristics. This is the first open dataset to address left- and right-handed motor imagery in acute stroke patients. We believe that the dataset will be very helpful for analysing brain activation and designing decoding methods that are more applicable for acute stroke patients, which will greatly facilitate research in the field of motor imagery-BCI.