Allergens induce upregulated IL-18 and IL-18Rα expression in blood Th2 and Th17 cells of patients with allergic asthma.

Allergic asthma (AA) is closely associated with the polarization of T helper (Th)2 and Th17 cells. Interleukin (IL)-18 acts as an inducer of Th2 and Th17 cell responses. However, expressions of IL-18 and IL-18 receptor alpha (IL-18Rα) in blood Th2 and Th17 cells of patients with AA remain unclear. We therefore investigated their expressions in Th2 and Th17 cells using flow cytometric analysis, qPCR and murine AA model. We observed increased proportions of Th2, Th17, IL-18+, IL-18+ Th2 and IL-18+ Th17 cells in blood CD4+ T cells of patients with AA. Additionally, house dust mite seemed to upregulate further IL-18 expression in Th2 and Th17, and upregulate IL-18Rα expression in CD4+ T, Th2 and Th17 cells of AA patients. It was also found that the plasma levels of IL-4, IL-17A and IL-18 in AA patients were elevated, and they were correlated between each other. In OVA-induced asthma mouse (AM), we observed that the percentages of blood CD4+ T, Th2 and Th17 cells were increased. Moreover, OVA-induced AM expressed higher level of IL-18Rα in blood Th2 cells, which was downregulated by IL-18. Increased IL-18Rα expression was also observed in blood Th2 cells of OVA-induced FcεRIα-/-mice. Collectively, our findings suggest the involvement of Th2 cells in AA by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy.

[Research progress of ICU-acquired weakness].

ICU-acquired weakness (ICU-AW) is a common complication in the intensive care unit (ICU). The occurrence of ICU-AW directly leads to prolonged ICU stays for critically ill patients, and in severe cases, it continues to affect their quality of life even after discharge. This article provides a comprehensive review of the research progress on ICU-AW based on domestic and foreign studies, aiming to provide a scientific overview of ICU-AW, including its definition, pathophysiology, diagnosis, screening tools, influencing factors, and potential intervention strategies, so as to promote timely planning and implementation of relevant screening and intervention measures.

Dexmedetomidine suppressed the biological behavior of RAW264.7 cells treated with LPS by down-regulating HOTAIR.

Background: Previous studies have revealed dexmedetomidine have potential protective effects on vital organs by inhibiting the release of inflammatory cytokines. To investigate the effects of dexmedetomidine on sepsis, especially in the initial inflammatory stage of sepsis. RAW264.7 cells were used as the cell model in this study to elucidate the underlying mechanisms. Methods: In this study, we conducted several assays to investigate the mechanisms of dexmedetomidine and HOTAIR in sepsis. Cell viability was assessed using the CCK-8 kit, while inflammation responses were measured using ELISA for IL-1ß, IL-6, and TNF-α. Additionally, we employed qPCR, MeRIP, and RIP to further explore the underlying mechanisms. Results: Our findings indicate that dexmedetomidine treatment enhanced cell viability and reduced the production of inflammatory cytokines in LPS-treated RAW264.7 cells. Furthermore, we observed that the expression of HOTAIR was increased in LPS-treated RAW264.7 cells, which was then decreased upon dexmedetomidine pre-treatment. Further investigation demonstrated that HOTAIR could counteract the beneficial effects of dexmedetomidine on cell viability and cytokine production. Interestingly, we discovered that YTHDF1 targeted HOTAIR and was upregulated in LPS-treated RAW264.7 cells, but reduced in dexmedetomidine treatment. We also found that YTHDF1 increased HOTAIR and HOTAIR m6A levels. Conclusions: Collectively, our results suggest that dexmedetomidine downregulates HOTAIR and YTHDF1 expression, which in turn inhibits the biological behavior of LPS-treated RAW264.7 cells. This finding has potential implications for the prevention and treatment of sepsis-induced kidney injury.

Multifunctionalized Supramolecular Cyclodextrin Additives Boosting the Durability of Aqueous Zinc-Ion Batteries.

The poor cycling stability of aqueous zinc-ion batteries hinders their application in large-scale energy storage due to uncontrollable dendrite growth and harmful hydrogen evolution reactions. Here, we designed and synthesized an electrolyte additive, N-methylimidazolium-ß-cyclodextrin p-toluenesulfonate (NMI-CDOTS). The cations of NMI-CD+ are more easily adsorbed on the abrupt Zn surface to regulate the deposition of Zn2+ and reduce dendrite generation under the combined action of the unique cavity structure with abundant hydroxyl groups and the electrostatic force. Meanwhile, p-toluenesulfonate (OTS-) is able to change the Zn2+ solvation structure and suppress the hydrogen evolution reaction by the strong interaction of Zn2+ and OTS-. Benefiting from the synergistic role of NMI-CD+ and OTS-, the Zn||Zn symmetric cell exhibits superior cycling performance as high as 3800 h under 1 mA cm-2 and 1 mA h cm-2. The Zn||V2O5 full battery also shows a high specific capacity (198.3 mA h g-1) under 2.0 A g-1 even after 1500 cycles, and its Coulomb efficiency is nearly 100% during the charging and discharging procedure. These multifunctional composite strategies open up possibilities for the commercial application of aqueous zinc-ion batteries.

Farrerol Alleviates Cerebral Ischemia-Reperfusion Injury by Promoting Neuronal Survival and Reducing Neuroinflammation.

Ischemia-reperfusion (I/R) injury is a key influencing factor in the outcome of stroke. Inflammatory response, oxidative stress, and neuronal apoptosis are among the main factors that affect the progression of I/R injury. Farrerol (FAR) is a natural compound that can effectively inhibit the inflammatory response and oxidative stress. However, the role of FAR in cerebral I/R injury remains unknown. In this study, we found that FAR reduced brain injury and neuronal viability after cerebral I/R injury. Meanwhile, administration of FAR also reduced the inflammatory response of microglia after brain injury. Mechanistically, FAR treatment directly reduced neuronal death after oxygen glucose deprivation/re-oxygenation (OGD/R) through enhancing cAMP-response element binding protein (CREB) activation to increase the expression of downstream neurotrophic factors and anti-apoptotic genes. Moreover, FAR decreased the activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, inhibited microglia activation, and reduced the production of inflammatory cytokines in microglia after OGD/R treatment or LPS stimulation. The compromised inflammatory response by FAR directly promoted the survival of neurons after OGD/R. In conclusion, FAR exerted a protective effect on cerebral I/R injury by directly decreasing neuronal death through upregulating CREB expression and attenuating neuroinflammation. Therefore, FAR could be a potentially effective drug for the treatment of cerebral I/R injury.

Chromatin target of protein arginine methyltransferases alleviates cerebral ischemia/reperfusion-induced injury by regulating RNA alternative splicing.

RNA splicing is a post-transcriptional event that regulates many physiological and pathological events. However, whether RNA splicing regulates cerebral I/R-induced brain injury remains largely unknown. In this study, we found that the chromatin target of Prmts (CHTOP) was highly expressed in neurons, and anti-inflammatory cytokine interleukin-10 (IL-10) upregulates its expression after ischemia. In addition, overexpression or knockdown of CHTOP alleviated or exacerbated neuronal death in both experimental stroke mice and cultured neurons. Mechanistically, RNA alternative splicing is altered early after oxygen and glucose deprivation/reoxygenation (OGD/R). CHTOP interacted with nuclear speckle-related proteins to regulate alternative mRNA splicing of neuronal survival-related genes after OGD/R. In addition, I/R injury-induced cytokines IL-10 regulate CHTOP-mediated RNA splicing to alleviate ischemic brain injury. Taken together, this study reveals the alteration of RNA splicing after OGD/R and identifies the IL-10-CHTOP-RNA splicing axis as a modulator of brain injury, which may be promising therapeutic targets for ischemic stroke.

CD8+ T cells in brain injury and neurodegeneration.

The interaction between the peripheral immune system and the brain is increasingly being recognized as an important layer of neuroimmune regulation and plays vital roles in brain homeostasis as well as neurological disorders. As an important population of T-cell lymphocytes, the roles of CD8+ T cells in infectious diseases and tumor immunity have been well established. Recently, increasing number of complex functions of CD8+ T cells in brain disorders have been revealed. However, an advanced summary and discussion of the functions and mechanisms of CD8+ T cells in brain injury and neurodegeneration are still lacking. Here, we described the differentiation and function of CD8+ T cells, reviewed the involvement of CD8+ T cells in the regulation of brain injury including stroke and traumatic brain injury and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and discussed therapeutic prospects and future study goals. Understanding these processes will promote the investigation of T-cell immunity in brain disorders and provide new intervention strategies for the treatment of brain injury and neurodegeneration.

Unconventional T cells in brain homeostasis, injury and neurodegeneration.

The interaction between peripheral immune cells and the brain is an important component of the neuroimmune axis. Unconventional T cells, which include natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, and other poorly defined subsets, are a special group of T lymphocytes that recognize a wide range of nonpolymorphic ligands and are the connection between adaptive and innate immunity. Recently, an increasing number of complex functions of these unconventional T cells in brain homeostasis and various brain disorders have been revealed. In this review, we describe the classification and effector function of unconventional T cells, review the evidence for the involvement of unconventional T cells in the regulation of brain homeostasis, summarize the roles and mechanisms of unconventional T cells in the regulation of brain injury and neurodegeneration, and discuss immunotherapeutic potential as well as future research goals. Insight of these processes can shed light on the regulation of T cell immunity on brain homeostasis and diseases and provide new clues for therapeutic approaches targeting brain injury and neurodegeneration.

Serum Cholinesterase, C-reactive Protein, Interleukin 6, and Procalcitonin Levels as Predictors of Mortality in Patients in the Intensive Care Unit.

Objective: The prognostic utility of inflammatory markers in survival has been suggested in patients with cancer; however, evidence on their prognostic value in severely ill patients is very limited. We aimed to explore the prognostic value of cholinesterase (ChE), C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT) in predicting mortality in patients from the intensive care unit (ICU). Methods: Serum levels of ChE, CRP, IL-6 and PCT were measured in ICU patients from December 13th, 2019 to June 28th, 2022. We assessed the predictive power of ChE, CRP, IL-6, and PCT using the receiver operating characteristic (ROC) curves. Furthermore, we evaluated their diagnostic accuracy by comparing the areas under the ROC curve (AUCs) along with their corresponding 95% confidence intervals (CIs). The cut-off values were determined to dichotomise these biomarkers, which were then included in multivariable logistic regression models to examine their relationship with ICU mortality. Results: Among 253 ICU patients included in the study, 66 (26%) died during the ICU stay. The AUCs to predict ICU mortality were 0.643 (95% CI, 0.566-0.719), 0.648 (95% CI, 0.633-0.735), 0.643 (95% CI, 0.563-0.723) and 0.735 (95% CI, 0.664-0.807) for ChE, CRP, IL-6 and PCT, respectively. After adjusting for age, sex and disease severity, lower ChE level (<3.668 × 103 U L-1) and higher levels of CRP (>10.546 mg dL-1), IL-6 (>986.245 pg mL-1) and PCT (>0.505 µg L-1) were associated with higher mortality risk, with odd ratios of 2.70 (95% CI, 1.32-5.54), 4.99 (95% CI, 2.41-10.38), 3.24 (95% CI, 1.54-6.78) and 3.67 (95% CI, 1.45-9.95), respectively. Conclusion: ChE, CRP, IL-6 and PCT were independent ICU mortality risk factors in severely ill patients. Elevated PCT levels exhibited better predictive value than the other three biomarkers that were evaluated.

Stochastic cooling notch filter developments for the high-precision spectrometer ring in the high intensity heavy-ion accelerator facility project.

Stochastic cooling of the high-precision spectrometer ring (SRing) at the High Intensity Heavy-Ion Accelerator Facility (HIAF) project in China, which is used mainly for experiments with radioactive fragment beams, is applied to speed up the cooling process of a stored ion beam. In this article, a new coaxial-type notch filter with an amplitude equalizer in the long branch and an optical-type notch filter with phase-stabilized optical fiber are discussed and evaluated for the SRing stochastic cooling system. Both prototypes of coaxial and optical notch filters are fabricated and tested. The minimum notch depth of coaxial and optical notch filters reaches to 26 and 40 dB, respectively. The performance of both coaxial notch filter and optical fiber notch filter is presented in this work. These developments will be used not only for the longitudinal stochastic cooling system but also have potential for the beam feedback system.

ACSL4 promotes microglia-mediated neuroinflammation by regulating lipid metabolism and VGLL4 expression.

Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an important isozyme in polyunsaturated fatty acid (PUFA) metabolism. The role of ACSL4 in the lipopolysaccharide (LPS)-induced inflammation of microglia, and the effects of ACSL4-mediated inflammation on the progression of Parkinson's disease (PD) are unknown. In this study, we found that ACSL4 expression was increased after LPS stimulation. Knocking down ACSL4 in microglia decreased proinflammatory cytokine production. Mechanistically, ACSL4 reduced vestigial-like family member 4(VGLL4) expression to promote NF-κB signal transduction; and ACSL4 regulated lipid composition after LPS stimulation. In addition, knocking down ACSL4 alleviated neuroinflammation in a systemic LPS model and acute l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) model. These data revealed ACSL4 to be a novel regulator that promotes microglia-mediated neuroinflammation by regulating VGLL4 expression and lipid metabolism.

Primary balloon angioplasty for chronic occlusion of intracranial internal carotid artery: A case report.

Chronic occlusion of large intracranial arteries is the main cause of ischemic stroke in China. Patients with symptomatic intracranial artery occlusion and hemodynamic impairment are at high risk of recurrent stroke. Chronic occlusion of the intracranial segment of the internal carotid artery is a common type of intracranial artery occlusion. Medical management is regarded as the standard treatment for this disease. With the development of endovascular treatment, some patients with chronic cerebral artery occlusion have achieved satisfactory results with endovascular therapy. We reported a patient with symptomatic chronic occlusion of the ophthalmic segment of the internal carotid artery. Simple balloon angioplasty was performed, and the occluded ophthalmic segment of the internal carotid artery was successfully recanalized without perioperative complications. At 4 months follow-up, the internal carotid artery remained patent and perfusion of the right cerebral hemisphere improved dramatically. In addition, we briefly reviewed the relevant literature.

Roles of peripheral immune cells in the recovery of neurological function after ischemic stroke.

Stroke is a leading cause of mortality and long-term disability worldwide, with limited spontaneous repair processes occurring after injury. Immune cells are involved in multiple aspects of ischemic stroke, from early damage processes to late recovery-related events. Compared with the substantial advances that have been made in elucidating how immune cells modulate acute ischemic injury, the understanding of the impact of the immune system on functional recovery is limited. In this review, we summarized the mechanisms of brain repair after ischemic stroke from both the neuronal and non-neuronal perspectives, and we review advances in understanding of the effects on functional recovery after ischemic stroke mediated by infiltrated peripheral innate and adaptive immune cells, immune cell-released cytokines and cell-cell interactions. We also highlight studies that advance our understanding of the mechanisms underlying functional recovery mediated by peripheral immune cells after ischemia. Insights into these processes will shed light on the double-edged role of infiltrated peripheral immune cells in functional recovery after ischemic stroke and provide clues for new therapies for improving neurological function.

Development of a diagonal-cut type beam position monitor for the booster ring in the High Intensity Heavy-Ion Accelerator Facility project.

A diagonal-cut type beam position monitor (BPM) has been developed for the High Intensity Heavy-Ion Accelerator Facility (HIAF) project at the Institute of Modern Physics. Compared with other types of BPMs, the diagonal-cut type BPM has almost perfect position linearity, i.e., no non-linear correction required, which is advantageous for beams that are transversally large and have a complex charge distribution. The key parameters for the diagonal-cut type BPM have been simulated and optimized in detail and systematically herein. It was found that the crosstalk is improved by ∼10 dB at 160 MHz by insertion of a separate ring between two horizontal or vertical electrodes of the BPM made of stainless steel with vacuum as a dielectric. Furthermore, the longitudinal and transverse numerical simulation to evaluate the beam impedance on the diagonal-cut type BPM has been performed. The results for the crosstalk, position sensitivity, and electrode capacitance to ground obtained from simulations and laboratory measurements agree well. The vacuum of the BPM prototype after baking out at 250 °C for 72 h is better than 1.0 × 10-11 mbar. The simulated and on-line measured BPM output signal magnitude results are consistent with each other. This diagonal-cut type BPM structure will be considered for application to the HIAF project as a priority.

The roles of methylprednisolone treatment in patients with COVID-19: A systematic review and meta-analysis.

The roles of methylprednisolone in treatment of patients with COVID-19 remain unclear. The aim of this study was to evaluate the efficacy and safety of methylprednisolone in treatment of COVID-19 patients. PubMed, Cochrane and Web of Science were searched for studies comparing methylprednisolone and no glucocorticoids treatment in patients with COVID-19. Statistical pooling was reported as risk ratio (RR) or mean difference (MD) with corresponding 95 % confidence interval (CI). Thirty-three studies were eligible, including 5 randomized trials and 28 observational studies. Meta-analysis showed that compared with no glucocorticoids, methylprednisolone in treatment of COVID-19 patients was associated with reduced short-term mortality (RR 0.73; 95% CI 0.60-0.89), less need for ICU admission (RR 0.77; 95% CI 0.66-0.91) and mechanical ventilation (RR 0.69; 95% CI 0.57-0.84), increased 28-day ventilator-free days (MD 2.81; 95% CI 2.64-2.97), without increasing risk of secondary infections (RR 1.04; 95% CI 0.82-1.32), but could prolong duration of viral shedding (MD 1.03; 95% CI 0.25-1.82). Subgroup analyses revealed that low-dose (≤2mg/kg/day) methylprednisolone treatment for ≤ 7 days in severe COVID-19 patients was associated with relatively better clinical outcomes, without increasing duration of viral shedding. Compared with no glucocorticoids, methylprednisolone treatment in COVID-19 patients is associated with reduced short-term mortality and better clinical outcomes, without increasing secondary infections, but could slightly prolong duration of viral shedding. Patients with severe COVID-19 are more likely to benefit from short-term low-dose methylprednisolone treatment (1-2 mg/kg/day for ≤ 7 days).

Multi-scale and attention enhanced graph convolution network for skeleton-based violence action recognition.

Graph convolution networks (GCNs) have been widely used in the field of skeleton-based human action recognition. However, it is still difficult to improve recognition performance and reduce parameter complexity. In this paper, a novel multi-scale attention spatiotemporal GCN (MSA-STGCN) is proposed for human violence action recognition by learning spatiotemporal features from four different skeleton modality variants. Firstly, the original joint data are preprocessed to obtain joint position, bone vector, joint motion and bone motion datas as inputs of recognition framework. Then, a spatial multi-scale graph convolution network based on the attention mechanism is constructed to obtain the spatial features from joint nodes, while a temporal graph convolution network in the form of hybrid dilation convolution is designed to enlarge the receptive field of the feature map and capture multi-scale context information. Finally, the specific relationship in the different skeleton data is explored by fusing the information of multi-stream related to human joints and bones. To evaluate the performance of the proposed MSA-STGCN, a skeleton violence action dataset: Filtered NTU RGB+D was constructed based on NTU RGB+D120. We conducted experiments on constructed Filtered NTU RGB+D and Kinetics Skeleton 400 datasets to verify the performance of the proposed recognition framework. The proposed method achieves an accuracy of 95.3% on the Filtered NTU RGB+D with the parameters 1.21M, and an accuracy of 36.2% (Top-1) and 58.5% (Top-5) on the Kinetics Skeleton 400, respectively. The experimental results on these two skeleton datasets show that the proposed recognition framework can effectively recognize violence actions without adding parameters.

Pharmacological inhibition of epidermal growth factor receptor attenuates intracranial aneurysm formation by modulating the phenotype of vascular smooth muscle cells.

AIM: To study the effect of pharmacological inhibition of epidermal growth factor receptor (EGFR) on intracranial aneurysm (IA) initiation. METHODS: Human IA samples were analyzed for the expression of p-EGFR and alpha smooth muscle actin (α-SMA) by immunofluorescence (IF). Rat models of IA were established to evaluate the ability of the EGFR inhibitor, erlotinib, to attenuate the incidence of IA. We analyzed anterior cerebral artery tissues by pathological and proteomic detection for the expression of p-EGFR and relevant proteins, and vessel casting was used to evaluate the incidence of aneurysms in each group. Rat vascular smooth muscle cells (VSMCs) and endothelial cells were extracted and used to establish an in vitro co-culture model in a flow chamber with or without erlotinib treatment. We determined p-EGFR and relevant protein expression in VSMCs by immunoblotting analysis. RESULTS: Epidermal growth factor receptor activation was found in human IA vessel walls and rat anterior cerebral artery walls. Treatment with erlotinib markedly attenuated the incidence of IA by inhibiting vascular remodeling and pro-inflammatory transformation of VSMC in rat IA vessel walls. Activation of EGFR in rat VSMCs and phenotypic modulation of rat VSMCs were correlated with the strength of shear stress in vitro, and treatment with erlotinib reduced phenotypic modulation of rat VSMCs. In vitro experiments also revealed that EGFR activation could be induced by TNF-α in human brain VSMCs. CONCLUSIONS: These results suggest that EGFR plays a critical role in the initiation of IA and that the EGFR inhibitor erlotinib protects rats from IA initiation by regulating phenotypic modulation of VSMCs.

MicroRNA-381-3p signatures as a diagnostic marker in patients with sepsis and modulates sepsis-steered cardiac damage and inflammation by binding HMGB1.

Immune response imbalance and cardiac dysfunction caused by sepsis are the main reasons for death in sepsis. This study aimed to confirm the expression and diagnostic possibility of microRNA-381-3p (miR-381-3p) and its mechanism in sepsis. Quantitative real-time PCR (qRT-PCR) and receiver operating characteristic (ROC) were used to reveal the levels and clinical significance of miR-381-3p. Pearson correlation was conducted to provide the correlations between miR-381-3p and several indexes of sepsis. The H9c2 cell models were constructed by lipopolysaccharide (LPS), and cecal ligation and puncture (CLP) was applied to establish the Sprague-Dawley (SD) rat models. Cell Counting Kit-8 (CCK-8) and flow cytometry were the methods to detect the cell viability and death rate of H9c2. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the concentration of inflammatory cytokines. The target gene of miR-381-3p was validated via the luciferase report system. The low expression of miR-381-3p was found in the serum of patients with sepsis. The lessened miR-381-3p could be a marker in the discrimination of sepsis patients. Overexpression of miR-381-3p could repress the mRNA expression of HMGB1, inhibit the cell apoptosis and inflammatory response, and motivate the viability of sepsis cells. At the same time, enhanced miR-381-3p promoted the inhibition of inflammation and cardiac dysfunction in the rat model of sepsis. Collectively, reduced levels of serum miR-381-3p can be used as an index to detect sepsis patients. MiR-381-3p restored the inflammatory response and myocardial dysfunction caused by sepsis via HMGB1.

Microglia and macrophage exhibit attenuated inflammatory response and ferroptosis resistance after RSL3 stimulation via increasing Nrf2 expression.

BACKGROUND: Many neurological diseases involve neuroinflammation, during which overproduction of cytokines by immune cells, especially microglia, can aggregate neuronal death. Ferroptosis is a recently discovered cell metabolism-related form of cell death and RSL3 is a well-known inducer of cell ferroptosis. Here, we aimed to investigate the effects of RSL3 in neuroinflammation and sensitivity of different type of microglia and macrophage to ferroptosis. METHODS: Here, we used quantitative RT-PCR analysis and ELISA analysis to analyze the production of proinflammatory cytokine production of microglia and macrophages after lipopolysaccharides (LPS) stimulation. We used CCK8, LDH, and flow cytometry analysis to evaluate the sensitivity of different microglia and macrophages to RSL3-induced ferroptosis. Western blot was used to test the activation of inflammatory signaling pathway and knockdown efficiency. SiRNA-mediated interference was conducted to knockdown GPX4 or Nrf2 in BV2 microglia. Intraperitoneal injection of LPS was performed to evaluate systemic inflammation and neuroinflammation severity in in vivo conditions. RESULTS: We found that ferroptosis inducer RSL3 inhibited lipopolysaccharides (LPS)-induced inflammation of microglia and peritoneal macrophages (PMs) in a cell ferroptosis-independent manner, whereas cell ferroptosis-conditioned medium significantly triggered inflammation of microglia and PMs. Different type of microglia and macrophages showed varied sensitivity to RSL3-induced ferroptosis. Mechanistically, RSL3 induced Nrf2 protein expression to inhibit RNA Polymerase II recruitment to transcription start site of proinflammatory cytokine genes to repress cytokine transcription, and protect cells from ferroptosis. Furthermore, simultaneously injection of RSL3 and Fer-1 ameliorated LPS-induced neuroinflammation in in vivo conditions. CONCLUSIONS: These data revealed the proinflammatory role of ferroptosis in microglia and macrophages, identified RSL3 as a novel inhibitor of LPS-induced inflammation, and uncovered the molecular regulation of microglia and macrophage sensitivity to ferroptosis. Thus, targeting ferroptosis in diseases by using RSL3 should consider both the pro-ferroptosis effect and the anti-inflammation effect to achieve optimal outcome.

ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation.

Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an important isozyme for polyunsaturated fatty acids (PUFAs) metabolism that dictates ferroptosis sensitivity. The role of ACSL4 in the progression of ischemic stroke is unclear. Here, we found that ACSL4 expression was suppressed in the early phase of ischemic stroke and this suppression was induced by HIF-1α. Knockdown of ACSL4 protected mice against brain ischemia, whereas, forced overexpression of ACSL4 exacerbated ischemic brain injury. ACSL4 promoted neuronal death via enhancing lipid peroxidation, a marker of ferroptosis. Moreover, knockdown of ACSL4 inhibited proinflammatory cytokine production in microglia. These data identify ACSL4 as a novel regulator of neuronal death and neuroinflammation, and interventions of ACSL4 expression may provide a potential therapeutic target in ischemic stroke.