Cuproptosis is a recently recognized modality of cell death driven by intracellular copper-dependent mitochondrial stress. However, the mediators of the sterile inflammatory response to cuproptotic death are undetermined. Here, we report that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern, is released by cuproptotic cells to initiate inflammation. Mechanically, copper accumulation-induced adenosine triphosphate (ATP) depletion activates AMP-activated protein kinase (AMPK) to promote HMGB1 phosphorylation, resulting in increased extracellular release. In contrast, genetic (using RNAi) or pharmacologic (using dorsomorphin) inhibition of AMPK activation limits cuproptosis and HMGB1 release. Functionally, the ability of HMGB1-deficient cuproptotic cells to promote advanced glycosylation end product-specific receptor (AGER, also known as RAGE)-dependent inflammatory cytokine production is greatly reduced. Thus, HMGB1 is a key immune mediator of cuproptosis-initiated sterile inflammation.

/pdf/hmgb1-is-a-mediator-of-cuproptosis-related-sterile-1cadw3ol.pdf

HMGB1 is a mediator of cuproptosis-related sterile inflammation

Intracerebral hemorrhage (ICH) is the second-largest stroke subtype and has a high mortality and disability rate. Secondary brain injury (SBI) is delayed after ICH. The main contributors to SBI are inflammation, oxidative stress, and excitotoxicity. Harmful substances from blood and hemolysis, such as hemoglobin, thrombin, and iron, induce SBI. When cells suffer stress, a critical protective mechanism called “autophagy” help to maintain the homeostasis of damaged cells, remove harmful substances or damaged organelles, and recycle them. Autophagy plays a critical role in the pathology of ICH, and its function remains controversial. Several lines of evidence demonstrate a pro-survival role for autophagy in ICH by facilitating the removal of damaged proteins and organelles. However, many studies have found that heme and iron can aggravate SBI by enhancing autophagy. Autophagy and inflammation are essential culprits in the progression of brain injury. It is a fascinating hypothesis that autophagy regulates inflammation in ICH-induced SBI. Autophagy could degrade and clear pro-IL-1β and apoptosis-associated speck-like protein containing a CARD (ASC) to antagonize NLRP3-mediated inflammation. In addition, mitophagy can remove endogenous activators of inflammasomes, such as reactive oxygen species (ROS), inflammatory components, and cytokines, in damaged mitochondria. However, many studies support the idea that autophagy activates microglia and aggravates microglial inflammation via the toll-like receptor 4 (TLR4) pathway. In addition, autophagy can promote ICH-induced SBI through inflammasome-dependent NLRP6-mediated inflammation. Moreover, some resident cells in the brain are involved in autophagy in regulating inflammation after ICH. Some compounds or therapeutic targets that regulate inflammation by autophagy may represent promising candidates for the treatment of ICH-induced SBI. In conclusion, the mutual regulation of autophagy and inflammation in ICH is worth exploring. The control of inflammation by autophagy will hopefully prove to be an essential treatment target for ICH.

Autophagy regulates inflammation in intracerebral hemorrhage: Enemy or friend?

METTL3 silenced inhibited the ferroptosis development via regulating the TFRC levels in the Intracerebral hemorrhage progression

mTOR and neuroinflammation in epilepsy: implications for disease progression and treatment

Neuroinflammation, characterized by the secretion of abundant inflammatory mediators, pro-inflammatory polarization of microglia, and the recruitment of infiltrating myeloid cells to foci of inflammation, drives or exacerbates the pathological processes of central nervous system disorders, especially in neurodegenerative diseases. Autophagy plays an essential role in neuroinflammatory processes, and the underlaying physiological mechanisms are closely correlated with neuroinflammation-related signals. Inhibition of mTOR and activation of AMPK and FOXO1 enhance autophagy and thereby suppress NLRP3 inflammasome activity and apoptosis, leading to the relief of neuroinflammatory response. And autophagy mitigates neuroinflammation mainly manifested by promoting the polarization of microglia from a pro-inflammatory to an anti-inflammatory state, reducing the production of pro-inflammatory mediators, and up-regulating the levels of anti-inflammatory factors. Notably, epigenetic modifications are intimately associated with autophagy and the onset and progression of various brain diseases. Non-coding RNAs, including microRNAs, circular RNAs and long noncoding RNAs, and histone acetylation have been reported to adjust autophagy-related gene and protein expression to alleviate inflammation in neurological diseases. The present review primarily focuses on the role and mechanisms of autophagy in neuroinflammatory responses, as well as epigenetic modifications of autophagy in neuroinflammation to reveal potential therapeutic targets in central nervous system diseases. 

Autophagy in Neuroinflammation: A Focus on Epigenetic Regulation.

HMGB1/TLR4 induces autophagy and promotes neuroinflammation after intracerebral hemorrhage

INTRODUCTION
Hemorrhagic transformation, especially symptomatic intracranial hemorrhage (sICH), is a common complication after mechanical embolectomy. This study explored a grading scale based on clinical and radiological parameters to predict sICH after mechanical embolectomy.


METHODS
Demographic and clinical data were retrospectively collected from patients with acute ischemic stroke treated with mechanical embolectomy at West China Hospital. Clinical and radiological factors associated with sICH were identified and used to develop the "STBA" grading scale. This score was then validated using data from an independent sample at the First Affiliated Hospital of Kunming Medical University.


RESULTS
We analyzed 268 patients with acute ischemic stroke who were treated with mechanical embolectomy at West China Hospital, of whom 30 (11.2%) had sICH. Patients were rated on an "STBA" score ranging from 0 to 6 based on whether systolic blood pressure was ≥145 mm Hg at admission (yes = 2 points; no = 0 points), time from acute ischemic stroke until groin puncture was ≥300 min (yes = 1; no = 0), blood glucose was ≥8.8 mmol/L (yes = 1; no = 0), and the Alberta Stroke Program Early Computed Tomography score at admission was 0-5 (2 points), 6-7 (1 point), or 8-10 (0 points). The STBA score showed good discrimination in the derivation sample (area under the receiver operating characteristic curve = 0.858) and in the validation sample (area = 0.814).


CONCLUSIONS
The STBA score may be a reliable clinical scoring system to predict sICH in acute ischemic stroke patients treated with mechanical embolectomy.

A Simple Grading Scale for Predicting Symptomatic Intracranial Hemorrhage after Mechanical Thrombectomy.

Differences in risk factors and outcome after acute stroke in patients with tandem occlusion and those with isolated intracranial occlusion after endovascular treatment

Purpose Systemic autoantibodies are important for the diagnosis of autoimmune diseases, but their roles in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis are unknown. The purpose of our study is to investigate the characteristics and a prognosis of anti-NMDAR encephalitis with the prevalence of autoantibodies. Methods Systemic autoantibodies were evaluated in 64 patients with anti-NMDAR encephalitis and 14 patients with autoimmune encephalitis with other forms. Then, according to systemic autoantibodies, patients with anti-NMDAR encephalitis were divided into an anti-nuclear antibody (ANA) positive group and an ANA negative group. The clinical outcome was assessed by a modified Rankin score at 12 months after the disease onset. Results A total of 64 patients with anti-NMDAR encephalitis were enrolled, of which 28.13% (18/64) were positive for ANA. The titers of a positive anti-NMDAR antibody in CSF (p = 0.041) and serum (p = 0.031) in the ANA-positive group were significantly higher than the ANA-negative group. Patients with ANA positive than those with ANA negative showed lower rates of headache (p = 0.047) and speech disorder (p = 0.049). The presence of ANA was associated with a worse clinical outcome at 12 months (p = 0.043). Conclusion ANA was prevalent in patients with anti-NMDAR encephalitis, and associated with a worse prognosis and impaired neurological recovery.

Presence of anti-nuclear antibody associated with worse clinical outcomes of anti-NMDAR encephalitis

Values of lymphocyte-related ratios in predicting the clinical outcome of acute ischemic stroke patients receiving intravenous thrombolysis based on different etiologies

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