During atherogenesis, macrophages turn into foam cells by engulfing lipids present within the atheroma plaques. The shift of foam cells toward proinflammatory or anti-inflammatory phenotypes, a critical step in disease progression, is still poorly understood. LXRs (liver X receptors) play a pivotal role in the macrophage response to lipid, promoting the expression of key genes of cholesterol efflux, mitigating intracellular cholesterol accumulation. LXRs also exert balanced actions on inflammation in human macrophages, displaying both proinflammatory and anti-inflammatory effects.

Our study explored the role of LXRs in the functional response of human macrophage to lipid-rich plaque environment. We used primary human macrophages treated with atheroma plaque extracts and assessed the impact of pharmacological LXR inhibition by GSK2033 on cholesterol homeostasis and inflammatory response. Ultimately, we evaluated macrophage and endothelial cell cross talk by assessing the impact of macrophage-conditioned supernatants on the human endothelial cell.

LXR inhibition by GSK2033 resulted in increased levels of cholesterol and oxysterols in human macrophages, alongside notable changes in the cholesterol ester profile. This was accompanied by heightened secretion of proinflammatory cytokines such as IL (interleukin)-6 and TNFα (tumor necrosis factor-α), despite a transcriptional repression of IL-1β. Conditioned media from GSK2033-treated macrophages more effectively activated ICAM-1 (intercellular adhesion molecule-1) and CCL2 (C-C motif ligand 2) expression in endothelial cells.

Our findings illustrate the intricate relationship between LXR function, cholesterol metabolism, and inflammation in human macrophages. While LXR is required for the proper handling of plaque lipids by macrophages, the differential regulation of IL-1β versus IL-6/TNFα secretion by LXRs could be challenging for potential pharmacological interventions.

Septic patients often face high mortality rates, influenced by various factors, including inflammation and nutritional status. This study investigates the relationship between the Advanced Lung Cancer Inflammation Index (ALI), an indicator of inflammation and nutritional status, and mortality rates (28-day, in-hospital, and ICU) in septic patients.

We conducted a retrospective analysis using data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, focusing on septic patients. Our primary analysis tools were multivariate logistic regression and restricted cubic spline (RCS) to examine the association between ALI and mortality outcomes. Additionally, subgroup and sensitivity analyses were performed to validate the findings.

The study included 3,739 septic patients. Results showed that higher ALI levels were significantly associated with reduced 28-day and in-hospital mortality rates. Specifically, a one-unit increment in natural log-transformed ALI was linked to a 16% reduced risk of 28-day mortality (p < 0.001) and a 12% reduced risk of in-hospital mortality (p = 0.002). These findings were consistent across different subgroups, confirming the stability of the results.

Elevated ALI levels are associated with lower mortality rates in septic patients, suggesting ALI as a potential prognostic marker for this group. However, further large prospective studies are needed to corroborate these findings and explore the implications for clinical practice.

The lung-brain axis represents a complex bidirectional communication network that is pivotal in the crosstalk between respiratory and neurological functions. This review summarizes the current understanding of the mechanisms and protein markers that mediate the effects of lung diseases on brain health.

In this review, we explore the mechanisms linking lung injury to neurocognitive impairments, focusing on neural pathways, immune regulation and inflammatory responses, microorganism pathways, and hypoxemia. Specifically, we highlight the role of the vagus nerve in modulating the central nervous system response to pulmonary stimuli; Additionally, the regulatory function of the immune system is underscored, with evidence suggesting that lung-derived immune mediators can traverse the blood-brain barrier, induce neuroinflammation and cognitive decline; Furthermore, we discuss the potential of lung microbiota to influence brain diseases through microbial translocation and immune activation; Finally, the impact of hypoxemia is examined, with findings indicating that it can exacerbate cerebral injury via oxidative stress and impaired perfusion. Moreover, we analyze how pulmonary conditions, such as pneumonia, ALI/ARDS, and asthma, contribute to neurological dysfunction. Prolonged mechanical ventilation can also contribute to cognitive impairment. Conversely, brain diseases (e.g., stroke, traumatic brain injury) can lead to acute respiratory complications. In addition, protein markers such as TLR4, ACE2, A-SAA, HMGB1, and TREM2 are crucial to the lung-brain axis and correlate with disease severity. We also discuss emerging therapeutic strategies targeting this axis, including immunomodulation and microbiome engineering. Overall, understanding the lung-brain interplay is crucial for developing integrated treatment strategies and improving patient outcomes. Further research is needed to elucidate the molecular mechanisms and foster interdisciplinary collaboration.

Kawasaki disease (KD) is an acute immune-mediated vasculitis primarily affecting coronary arteries, with limited specific diagnostic biomarkers available. Chitinase protein-40 (YKL-40), a glycoprotein secreted by neutrophils and macrophages, has been associated with vascular inflammation in cardiovascular diseases. This study aimed to investigate the role of YKL-40 in KD by analyzing its serum levels, correlations with inflammatory markers, and potential as a diagnostic and prognostic biomarker.

Serum YKL-40 and interleukin-6 (IL-6) levels were measured using enzyme-linked immunosorbent assay (ELISA) in 46 children with KD (16 with coronary artery lesions [CAL], 30 without CAL) and 30 healthy controls. Correlations between YKL-40, IL-6, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell (WBC) count, and platelet (PLT) levels were analyzed.

YKL-40, IL-6, CRP, ESR, WBC, and PLT levels were significantly elevated in KD patients compared to controls. YKL-40 levels correlated positively with IL-6, CRP, and ESR. A serum YKL-40 threshold of ≥ 71.930 ng/mL predicted CAL with sensitivity and specificity of 0.875 and 0.800, respectively. Combining YKL-40 with IL-6 improved sensitivity and specificity to 0.938 and 0.833.

YKL-40 is significantly elevated in KD and correlates with inflammatory markers, suggesting its involvement in disease pathogenesis. It is a promising inflammatory biomarker and independent risk factor for predicting CAL in KD, offering potential for improved diagnosis and prognosis.

Not applicable.

Xuebijing (XBJ) injection is a Traditional Chinese medicine (TCM) injection extracted and prepared using modern TCM formulation techniques. As a widely used treatment for critically ill patients, XBJ injection has shown significant therapeutic effects in clinical applications in China. It plays an indispensable role in sepsis-induced myocardial dysfunction (SIMD). However, its underlying mechanisms require further investigation.

This study aims to investigate the cardioprotective effects of XBJ in sepsis and to elucidate its underlying mechanisms.

Network pharmacology was used to predict the potential active components and core targets of XBJ against SIMD. Furthermore, animal models were used to verify its pharmacodynamics. Metabolomics was integrated to track the myocardial tissue metabolites from septic rats. Molecular docking, qRT-PCR, Western blot, and immunofluorescence were performed to investigate the mechanisms of action.

Network pharmacology predicted that the efficacy of XBJ is attributed to 104 active components and 178 targets. Metabolomics of myocardial tissue from CLP rats revealed that the key metabolic pathways included the tricarboxylic acid (TCA) cycle, pyrimidine metabolism, and purine metabolism. Five core active components of XBJ (quercetin, luteolin, rutin, β-sitosterol, and cryptotanshinone) can modulate interleukin-6 (IL-6), epidermal growth factor receptor (EGFR), B-cell lymphoma 2 (BCL2), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and hypoxia-inducible factor 1-alpha (HIF-1α). Molecular docking analysis confirmed that the core components of XBJ have a strong affinity for these key targets. Additionally, qRT-PCR, Western blotting, and immunofluorescence results indicated that XBJ can reverse the expression of these targets, ameliorated energy metabolism dysregulation, and alleviated SIMD.

XBJ exerts protective effects in a rat model of sepsis-induced myocardial injury, by modulating energy metabolism pathways that regulate key SIMD-related targets (IL-6, EGFR, BCL2, PGC-1α, and HIF-1α), thereby improving myocardial energy metabolism and alleviating inflammatory responses.

Astrocytes play a pivotal role in the inflammatory response triggered by traumatic brain injury (TBI). They are not only involved in the initial inflammatory response following injury but also significantly contribute to Astrocyte activation and inflammasome release are key processes in the pathophysiology of TBI, significantly affecting the progression of secondary injury and long-term outcomes. This comprehensive review explores the complex triggering mechanisms of astrocyte activation following TBI, the intricate pathways controlling the release of inflammasomes from activated astrocytes, and the subsequent neuroinflammatory cascade and its multifaceted roles after injury. The exploration of these processes not only deepens our understanding of the neuroinflammatory cascade but also highlights the potential of astrocytes as critical therapeutic targets for TBI interventions. We then evaluate cutting-edge research aimed at targeted therapeutic approaches to modulate pro-inflammatory astrocytes and discuss emerging pharmacological interventions and their efficacy in preclinical models. Given that there has yet to be a relevant review elucidating the specific intracellular mechanisms targeting astrocyte release of inflammatory substances, this review aims to provide a nuanced understanding of astrocyte-mediated neuroinflammation in TBI and elucidate promising avenues for therapeutic interventions that could fundamentally change TBI management and improve patient outcomes. The development of secondary brain injury and long-term neurological sequelae. By releasing a variety of cytokines and chemokines, astrocytes regulate neuroinflammation, thereby influencing the survival and function of surrounding cells. In recent years, researchers have concentrated their efforts on elucidating the signaling crosstalk between astrocytes and other cells under various conditions, while exploring potential therapeutic interventions targeting these cells. This paper highlights the specific mechanisms by which astrocytes produce inflammatory mediators during the acute phase post-TBI, including their roles in inflammatory signaling, blood-brain barrier integrity, and neuronal protection. Additionally, we discuss current preclinical and clinical intervention strategies targeting astrocytes and their potential to mitigate neurological damage and enhance recovery following TBI. Finally, we explore the feasibility of pharmacologically assessing astrocyte activity post-TBI as a biomarker for predicting acute-phase neuroinflammatory changes.

Checkpoint inhibitor therapies do not benefit all patients, and adjuvants play a critical role in boosting immune responses for effective cancer immunotherapy. However, their systemic toxicity and suboptimal activation kinetics pose significant challenges. Here, this study presented a linker-based strategy to modulate the activation kinetics of Toll-like receptor 7/8 (TLR7/8) agonists delivered via poly (propylene sulfide) nanoparticles (PPS NPs). By covalently binding small molecule TLR7/8 agonists to PPS NPs with different linkers, enhanced therapeutic efficacy is achieved while abrogating systemic toxicity. These results showed that an alkyl linker selectively prolong the activation of DCs. It avoided the extensive activation of other APCs, favoring the limitation of immune-related toxicities. This strategy exhibited significant anti-tumor activity in alkyl linked nano-TLR7/8 agonists treatment alone, and cytokine and immune cell profiling provided evidence of prolonged immune cell activation in the tumor microenvironment, with evidence of an increase in the frequency of tumor antigen-specific CD8+ T cells. This linker-based approach offers a promising strategy to optimize the delivery of nano-TLR7/8 agonists for cancer immunotherapy, potentially advancing the field toward improved clinical outcomes.

Vasculitis is a group of syndromes characterized by inflammation, presence of autoantibodies and endothelial cells (ECs) damage, which lead to stenosis or occlusion of the vascular lumen. Anti-endothelial cell antibodies (AECAs) are a heterogeneous group of autoantibodies in vasculitis. AECAs bind to antigens and membrane-bound proteins of ECs, inducing inflammation, coagulation, and apoptosis. In this review, we discuss the pathological role of AECAs in different types of vasculitis. In addition, AECAs potentially induce alterations of ECs mechanical properties, and subsequently promotes angiogenic phenotypes in the occurrence of vasculitis.

The COVID-19 pandemic remains a global health challenge. Severe cases often respond poorly to standard treatments, highlighting the necessity for novel therapeutic targets and early predictive biomarkers.

We utilized flow cytometry to analyze peripheral immune cells from healthy, bacterial pneumonia patients, and COVID-19 patients. The expansion of activated T cells (CD38+HLA-DR+), monocytes, and myeloid-derived suppressor cells (MDSCs) were detected and correlated with clinical outcomes to evaluate prognostic potential. The single-cell RNA sequencing (scRNA-seq) was applied to characterize the critical cell subset associated with prognosis and elucidate its phenotype in COVID-19.

We revealed a significant increase in CD38+HLA-DR+ T cells in non-survivor COVID-19 patients, establishing them as an independent risk factor for 28-day mortality. The scRNA-seq analysis identified the CD38+HLA-DR+ T cell as a terminally differentiated, Treg-like subset exhibiting both activation and exhaustion characteristics. This subset presented the highest IL-6 and IL-10 mRNA levels among all T-cell subsets. Further functional analysis demonstrated its enhanced major histocompatibility complex class II (MHC-II) cross-signaling and correspondingly enriched cytoskeletal rearrangement processes. In addition, there was dysregulated NAD+ metabolism in CD38+HLA-DR+ T cells via scRNA-seq, accompanied by elevated adenosine and decreased NAD+ levels in serums from COVID-19 patients.

We identified the selective expansion of CD38+HLA-DR+ T cells as a novel prognostic indicator for COVID-19 outcomes. These cells' unique activated-exhausted phenotype, along with their impact on NAD+ metabolism, provides new insights into COVID-19 immunopathogenesis.

Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disorder characterised by systemic inflammation resulting from overproduction of interleukin 6 (IL-6). While iMCD primarily affects the lymph nodes and related tissues, it can also rarely involve the central nervous system.

We report the case of a 58-year-old female patient with at least a 3-year history of iMCD, who experienced acute thunderclap headaches due to reversible cerebral vasoconstriction syndrome (RCVS). RCVS occurred 3 months after initiating treatment with tocilizumab, a humanised anti-IL-6 receptor monoclonal antibody, and was accompanied by focal cortical subarachnoid haemorrhage (SAH). Elevated IL-6 levels were found in both serum and cerebrospinal fluid. MR angiography revealed multiple diffuse stenotic lesions in the bilateral middle and posterior cerebral arteries, which, along with bilateral cerebral oedema, resolved within 3 months. The diffuse nature of the cerebral vasospasm and the presence of bilateral brain oedema suggested that cerebral vasospasm was due to RCVS rather than SAH.

In patients with Castleman disease, RCVS may occur due to IL-6-dependent chronic cerebral vascular inflammation, either as a primary condition or as a complication of tocilizumab treatment.

Acute macular neuroretinopathy (AMN) is a rare retinal condition that predominantly affects young females. The incidence of AMN increased significantly during the COVID-19 pandemic, thereby providing a unique opportunity to elucidate the etiology of this disease. In the present study, 24 articles reporting 59 patients were reviewed. The average age of the patients was 33.51 ± 14.02 years, ranging from 16 to 75 years, with females comprising 71.19% of the cases. The average duration of ocular symptoms post-infection was 8.22 ± 10.69 days, ranging from 4 to 150 days. This study investigated the potential pathogenesis of AMN, including the impact of COVID-19 on retinal neurovascular structure and function, immune-mediated inflammatory factor production, blood-retinal barrier disruption, and retinal microvascular damage, as well as potential clinical therapeutic interventions. This research provides a theoretical framework that can inform further investigations of AMN.

Cytokine storm (CS) is a severe systemic inflammatory syndrome characterized by the excessive activation of immune cells and a significant increase in circulating levels of cytokines. This pathological process is implicated in the development of life-threatening conditions such as fulminant myocarditis (FM), acute respiratory distress syndrome (ARDS), primary or secondary hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS) associated with chimeric antigen receptor-modified T (CAR-T) therapy, and grade III to IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. The significant involvement of the JAK-STAT pathway, Toll-like receptors, neutrophil extracellular traps, NLRP3 inflammasome, and other signaling pathways has been recognized in the pathogenesis of CS. Therapies targeting these pathways have been developed or are currently being investigated. While novel drugs have demonstrated promising therapeutic efficacy in mitigating CS, the overall mortality rate of CS resulting from underlying diseases remains high. In the clinical setting, the management of CS typically necessitates a multidisciplinary team strategy encompassing the removal of abnormal inflammatory or immune system activation, the preservation of vital organ function, the treatment of the underlying disease, and the provision of life supportive therapy. This review provides a comprehensive overview of the key signaling pathways and associated cytokines implicated in CS, elucidates the impact of dysregulated immune cell activation, and delineates the resultant organ injury associated with CS. In addition, we offer insights and current literature on the management of CS in cases of FM, ARDS, systemic inflammatory response syndrome, treatment-induced CRS, HLH, and other related conditions.

SARS-CoV-2 has demonstrated a remarkable capacity for immune evasion. While initial studies focused on the Wuhan variant and adaptive immunity, later emerging strains such as Omicron exhibit mutations that may alter their immune-modulatory properties. We performed a comprehensive review of immune evasion mechanisms associated with SARS-CoV-2 viral proteins to focus on the evolutionary dynamics of immune modulation. We systematically analyzed and compared the impact of all currently known Wuhan and Omicron SARS-CoV-2 proteins on type I interferon (IFN) responses using a dual-luciferase reporter assay carrying an interferon-inducible promoter. Results revealed that Nsp1, Nsp5, Nsp14, and ORF6 are potent type I IFN inhibitors conserved across Wuhan and Omicron strains. Notably, we identified strain-specific differences, with Nsp6 and Spike proteins exhibiting enhanced IFN suppression in Omicron, whereas the Envelope protein largely retained this function. To extend these findings, we investigated selected proteins in primary human endothelial cells and also observed strain-specific differences in immune response with higher type I IFN response in cells expressing the Wuhan strain variant, suggesting that Omicron's adaptational mutations may contribute to a damped type I IFN response in the course of the pandemic's trajectory.

COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) as a pandemic infectious disease. So far, it has been known that this virus uses several receptors to enter the host cell, one of which is neuropilin-1 (NRP1). Also, one of the main causes of clinical manifestations, severity of disease, and mortality of patients is cytokine storm syndrome, one of these cytokines being interleukin (IL)-6. Our aim was to study the level of expression of NRP1 and IL-6 genes in COVID-19 patients by using peripheral blood mononuclear cells (PBMCs).

Our study population included the test group (80 patients with COVID-19) and the control group (30 healthy individuals). Venous blood was taken from all subjects. After isolating PBMCs from blood using Ficoll, RNA was extracted. Then, cDNA synthesis, the expression level of NRP1 and IL-6 compared to GAPDH housekeeping gene was measured by real-time PCR.

The level of NRP1 gene expression was increased significantly in COVID-19 different groups compared to the control group. Surprisingly, it was observed that the amount of NRP1 gene decreased in the vaccinated group compared to nonvaccinated groups. IL-6 gene expression was also significantly increased in all groups except vaccinated patients compared to the control group. Also, the results indicated that there was a positive and statistically considerable relationship between IL-6 expression level and NRP1 expression level (p = 0.03).

The significant increase in the expression of NRP1 and IL-6 genes in COVID-19 patients, especially in moderate and severe cases, indicates their potential involvement in the progression of the disease, which may serve as biomarkers of disease severity. Also, since these genes play an important role in causing severe inflammation, cytokine storm, and immunopathological complications of COVID-19, further investigations maybe needed to achieve therapeutic goals to control COVID-19 and similar diseases.

The term early life stress encompasses traumatic events occurring before the age of 18 years, such as physical abuse, verbal abuse, household dysfunctions, sexual abuse, childhood neglect, child maltreatment, and adverse childhood experiences. Adverse psychological experiences in early life are linked to enduring effects on mental and physical health in adulthood. In this review, we first describe the effects and potential mechanisms of early life stress on the components of the vasculature. Next, we dive into the impact of early life stress on the vasculature across the lifespan through alterations of the epigenetic landscape. Finally, we consolidate the critical gaps in knowledge for focusing future research including the potential for resilience in combatting the impact of early life stress on vascular health.

The pathophysiology of a stroke is a complex process involving oxidative stress and inflammation. As a result of the actions of reactive oxygen species (ROS), not only does vascular damage occur, but the brain tissue is also damaged. It is a dynamic process, induced by a cellular-molecular immune response, focused on the development of an immediate reaction. During ischemia, inflammatory mediators are released, among which IL-6 plays a particularly important role in the acute phase of a stroke. Recently, a lot of attention has been devoted to this pleiotropic pro-inflammatory cytokine, which enhances the migration of leukocytes and is controlled by chemokines and the expression of adhesion handlers. The impact of IL-6 on the severity of neurological treatment and on patient prognosis in AIS is of interest to many researchers. More and more data indicate that it may be a reliable prognostic factor in strokes.

In sepsis, acute lung injury (ALI) is a severe complication and a leading cause of death, involving complex mechanisms that include cellular and molecular interactions between immune and lung parenchymal cells. In recent decades, the role of Toll-like receptor 4 (TLR4) in mediating infection-induced inflammation has been extensively studied. However, how TLR4 facilitates interactions between innate immune cells and lung parenchymal cells in sepsis remains to be fully understood. This study aims to explore the role of TLR4 in regulating macrophage immunity and metabolism in greater depth. It also seeks to reveal how changes in these processes affect the interaction between macrophages and both pulmonary endothelial cells (ECs) and lymphatic endothelial cells (LECs). Using TLR4 knockout mice and the combined approaches of single-cell RNA sequencing and experimental validation, we demonstrate that in sepsis, TLR4-deficient macrophages upregulate Abca1, enhance cholesterol efflux, and reduce glycolysis, promoting M2 polarization and attenuating inflammation. These metabolic and phenotypic shifts significantly affect their interactions with pulmonary ECs and LECs. Mechanistically, we uncovered that TLR4 operates through multiple pathways in endothelial dysfunction: macrophage TLR4 mediates inflammatory damage to ECs/LECs, while endothelial TLR4 both directly sensitizes cells to lipopolysaccharide-induced injury and determines their susceptibility to macrophage-derived inflammatory signals. These findings reveal the complex role of TLR4 in orchestrating both immune-mediated and direct endothelial responses during sepsis-induced ALI, supporting that targeting TLR4 on multiple cell populations may present an effective therapeutic strategy.

Maternal immune activation (MIA) is a principal environmental risk factor contributing to autism spectrum disorder (ASD) and can be causally linked to ASD symptoms. In our study, we found that MIA triggered by poly (I: C) injection caused ventriculomegaly in offspring due to the dysfunction of the choroid plexus (Chp) and ependyma. We subsequently identified a sustained enhancement of interferon-γ (IFN-γ) signaling in the brain and serum of MIA offspring. Further study revealed that increased IFN-γ signaling could disrupt the barrier function of Chp epithelial cells by activating macrophages, and suppress the differentiation of primary ependymal cells via the signal transducer and activator of transcription 1/3 signaling. The effects of MIA on the offspring were mitigated by administration of IFNGR-blocking antibody in pregnant dams, while systemic maternal administration of IFN-γ was sufficient to mimic the effect of MIA. Overall, our findings revealed that ventriculomegaly caused by IFN-γ signaling could be a critical factor in compromising fetal brain development in MIA-induced ASD and provide a mechanistic framework for the association between maternal inflammation and abnormal development of ventricles in the offspring.

Interleukin-6 (IL-6) is a critical cytokine involved in immune regulation, inflammation, and the pathogenesis of various diseases, including autoimmune disorders, cancer, and the cytokine storm associated with severe COVID-19. Identifying IL-6 inducing epitopes, the short peptide fragments that trigger IL-6 production, is crucial for developing epitope-based vaccines and immunotherapies. However, traditional methods for epitope prediction often lack accuracy and efficiency. This study presents RAG_MCNNIL6, a novel deep learning framework that integrates Retrieval-augmented generation (RAG) with multiwindow convolutional neural networks (MCNNs) for accurate and rapid prediction of IL-6 inducing epitopes. RAG_MCNNIL6 leverages ProtTrans, a state-of-the-art pretrained protein language model, to generate rich embedding representations of peptide sequences. By incorporating a RAG-based similarity retrieval and embedding augmentation strategy, RAG_MCNNIL6 effectively captures both local and global sequence patterns relevant for IL-6 induction, significantly improving prediction performance compared to existing methods. We demonstrate the superior performance of RAG_MCNNIL6 on benchmark data sets, highlighting its potential for advancing research and therapeutic development for IL-6-mediated diseases.

Introduction: Cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) are both serious complications of CAR-T therapy associated with endothelial dysfunction, prompting prior use of a modified version of the endothelial activation and stress index (m-EASIX) to predict the occurrence of severe ICANS and CRS. Previous studies have linked both hypophosphatemia and elevated IL6 levels to CRS and ICANS. Our study aimed to enhance the early prediction of both syndromes by integrating phosphorous and IL-6 both together and separately into the m-EASIX score. Methods: Forty-two patients with non-Hodgkin's lymphoma presenting for CAR-T treatment were used to generate three variations in the m-EASIX score, assessing performance for the clinically actionable time points of day +0 through day +3. Results: The addition of phosphorous through the P-m-EASIX improved the predictive capabilities for the occurrence of ICANS, most notably on day +1 (AUC 89.6%; p = 0.0090, OR of 2.23; p = 0.0096) compared to the m-EASIX (AUC 80.8%; p = 0.0047, OR 1.72; p = 0.0046). The P-m-EASIX also showed enhanced predictive capabilities for the occurrence of CRS, with peak discriminatory function on day +3 (AUC 92.0%; p = <0.0001, OR 2.21; p = 0.0014). The addition of IL6 in the IL6-m-EASIX showed the highest discriminatory capacity for the prediction of CRS progression to grade ≥ 2 with peak function on day +3 (AUC 89.7%; p = 0.0040, OR 1.57; p = 0.031). Conclusions: Incorporating phosphorus levels into the m-EASIX score offered a cost-effective and straightforward method to improve the prediction of CAR-T toxicities. Larger-scale studies assessing the effectiveness of including phosphorus and IL-6 in the m-EASIX score to mitigate complications associated with CAR-T therapy are warranted.

Coronavirus disease 2019 (COVID-19) is a multi-system disease that can lead to various severe complications. Acute limb ischemia (ALI) has been increasingly recognized as a COVID-19-associated complication that often predicts a poor prognosis. However, the pathophysiology and molecular mechanisms underlying COVID-19-associated ALI remain poorly understood. Hypercoagulability and thrombosis are considered important mechanisms, but we also emphasize the roles of vasospasm, hypoxia, and acidosis in the pathogenesis of the disease. The angiotensin-converting enzyme 2 (ACE2) pathway, inflammation, and platelet activation may be important molecular mechanisms underlying these pathological changes induced by COVID-19. Furthermore, we discuss the hypotheses of risk factors for COVID-19-associated ALI from genetic, age, and gender perspectives based on our analysis of molecular mechanisms. Additionally, we summarize therapeutic approaches such as use of the interleukin-6 (IL-6) blocker tocilizumab, calcium channel blockers, and angiotensin-converting enzyme inhibitors, providing insights for the future treatment of coronavirus-associated limb ischemic diseases.

Sepsis-associated encephalopathy (SAE) is a complication of impaired neurologic function during the development of sepsis. Its occurrence is closely related to severe systemic infection. The increase of serum Interleukin 6 kit and other inflammatory cytokines has certain clinical significance in the diagnosis of sepsis, However, there is no research at home or abroad indicating whether the high expression of related inflammatory cytokines (inflammatory cytokine storm, ICS) is valuable for the diagnosis and prognosis of SAE patients.

The aim of this study was to analyze serum inflammatory cytokines 6 kit [IL-2/4/6/10, TNF-α, and gamma interferon (IFN-γ)], heparin-binding protein (HBP), and serum cholinesterase levels and their clinical significance in septic patients. In this study, we defined the values of inflammatory storm (IL-6 > 5000 pg/ml, IL-10 > 1000 pg/ml, and HBP > 300 ng/ml) to analyze the diagnostic value and 28-day prognostic predictive ability of inflammatory cytokine storm and the severity score in SAE patients.

A total of 140 patients with sepsis in the ICU and EICU of the Lianyungang First People's Hospital were included in the present study from October 2021 to March 2023. Based on the Diagnostic criteria for SAE, the 140 cases were divided into 62 cases in the SAE group and 78 cases in the non-SAE group. On admission to the ICU/EICU, the patients gender, age, vital signs, and serum levels of various cytokines were recorded. The Glasgow Coma Scale (GCS), Sequential Organ Failure Scale (SOFA), and Acute Physiological and Chronic Health Score II (APACHE-II) scores were also assessed to analyze the risk cytokines for the occurrence of SAE.

The age, Sofa score, APACHE-II score, 28-day mortality rate, serological cellular inflammatory cytokines (IL-2/6/10, INF-α, and interferon-gamma), HBP were significantly higher in the SAE group than in the non-SAE group (P < 0.05). In addition, the GCS score and serum cholinesterase levels in the SAE group were lower than in the non-SAE group (P < 0.05). Subsequently, Multi-factor logistic regression analysis revealed that ultra-high IL-6 (> 5000 pg/ml), IL-10 (> 1000 pg/ml), and HBP (> 300 ng/ml) levels and elevated SOFA and APACHE-II scores were risk cytokines for the development of SAE (P < 0.05). 28-day mortality was significantly higher in patients in the SAE group and in the IL-6 > 5000 pg/ml group compared to patients in the USAE and IL-6 < 5000 pg/ml groups(P < 0.001).The four screened predictors of HBP > 300 ng/ml, IL-6 > 5000 pg/ml, decreased GCS score, and decreased APACHEII score were combined into a new predictive data model (risk score).In the SAE group, patients with high risk scores had a higher 28-day mortality rate compared with the low risk score group (P < 0.001).

The occurrence of SAE is closely correlated with age, concomitant diabetes, SOFA score, APACHE II score, serum cytosolic inflammatory cytokine levels (IL-2/6/10, TNF-α, and IFN-γ), HBP, and serum cholinesterase levels. In addition, inflammatory storms are associated with the mechanism of SAE, and high expression levels of the inflammatory cytokines IL-6 > 5000 pg/ml, IL-10 > 1000 pg/ml, and HBP > 300 ng/ml in patients with sepsis contribute to the early diagnosis of SAE. In addition, IL-6 > 5000 pg/ml was also associated with an increase in 28-day mortality (P < 0.05), suggesting that the level of inflammatory storms may be related to the mechanism of sepsis-related SAE and 28-day mortality. According to the LASSO results, when SAE patients admitted to the intensive care unit satisfy HBP > 300 ng/ml, IL6 > 5000 pg/ml, decreased GCS score, and increased APACHEII score, it suggests that the patient's 28-day mortality rate is higher, and it also validates that inflammatory storm can be used as a predictor of prognosis for SAE patients.

Spinal cord injury (SCI), characterized by the disruption of neural pathways and an increase in inflammatory cell infiltration, leads to profound and lasting neurological deficits, with a high risk of resulting in permanent disability. Currently, the therapeutic landscape for SCI is notably sparse, with limited effective treatment options available. Methylprednisolone (MP), a widely used clinical anti-inflammatory agent for SCI, requires administration in high doses that are associated with significant adverse effects. In this study, we introduce an innovative approach by substituting cholesterol with MP to engineer a novel Lipid Nanoparticle (MP-LNP). This strategy aims to enhance the localization and concentration of MP at the injury site, thereby amplifying its therapeutic efficacy while mitigating systemic side effects. Furthermore, we explore the integration of C3 transferase mRNA into MP-LNPs. C3 transferase, a potent inhibitor of the RhoA pathway, has shown promise in facilitating neurological recovery in animal models of SCI and is currently being evaluated in clinical trials. The novel formulation, MP-LNP-C3, is designed for direct administration to the injury site during decompression surgery, offering a targeted therapeutic modality for SCI. Our findings reveal several significant advantages of this approach: Firstly, the incorporation of C3 transferase mRNA into MP-LNPs does not compromise the structural integrity of the nanoparticles, ensuring efficient mRNA expression within the spinal cord. Secondly, the MP-LNP formulation effectively attenuates inflammation and reduces the adverse effects associated with high-dose MP treatment in the acute phase of SCI. Lastly, MP-LNP-C3 demonstrates notable neuroprotective properties and promotes enhanced recovery of motor function in SCI mouse models. Together, these results underscore the potential of this innovative LNP-based therapy as a promising avenue for advancing the treatment of clinical SCI.

Dengue virus infection can cause severe complications due to vascular leakage. Angiopoietin-like protein 4 (ANGPTL4) regulates vascular permeability, but its role in dengue pathogenesis is unclear. This study investigated the association between plasma ANGPTL4 levels and dengue severity in Singapore adults. Plasma samples from 48 dengue patients (24 severe and 24 non-severe) during acute and convalescent phases were selected from the prospective COhort study on progression of DENgue severity in Singapore adults (CODEN) cohort. The CODEN was conducted at the National Centre for Infectious Diseases, Tan Tock Seng Hospital, from June 2016 to January 2020. ANGPTL4 levels were measured and compared to 152 healthy controls. Logistic regression assessed the relationship between plasma ANGPTL4 concentrations and disease severity. There were no statistically significant differences in ANGPTL4 levels between severe and non-severe dengue patients during acute (677.4 vs. 909.1 pg/mL, p = 0.4) or convalescent phases (793.7 vs. 565.6 pg/mL, p = 0.96). Plasma ANGPTL4 levels were significantly elevated during acute dengue (4634.3 pg/mL) versus healthy controls (907.4 pg/mL), declining during convalescence. Compared to the lowest tertile, the adjusted odds ratios for severe dengue were 0.36 (95%CI: 0.08-1.65, p = 0.190) for medium tertile and 0.57 (95%CI: 0.13-2.49, p = 0.456) for high tertile. Among patients with high ANGPTL4 levels (>5000 pg/mL), 36.4% developed severe complications, including significant plasma leakage. Plasma ANGPTL4 levels were significantly higher in dengue patients than controls, suggesting its potential as a biomarker, which warrants future detailed investigations. Larger prospective studies with serial sampling, including pediatric populations, may clarify the role of ANGPTL4 in severe dengue.

Reversion inducing cysteine rich protein with kazal motifs (RECK), a Kazal motif-containing protein, regulates pro-inflammatory cytokines production, migration of inflammatory cells, vascular endothelial growth factor (VEGF) and Wnt pathways and plays critical roles in septic inflammatory storms and vascular endothelial dysfunction. Recently, RECK has been defined as the negative regulator of adisintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs), which are both membrane "molecular scissors" and aggravate the poor prognosis of sepsis. To better understand the roles of RECK and the related mechanisms, we make here a systematic and in-depth review of RECK. We first summarize the findings on structural characteristics of RECK protein and the regulation at the transcription, post-transcription, or protein level of RECK. Then, we discuss the roles of RECK in inflammation, infection, and vascular injury by focusing on the RECK function on ADAMs and MMPs, as well as the pathways of VEGF, WNT, angiopoietin, and notch signaling. In conclusion, RECK participation as a guardian in the development of sepsis provides insight into the strategies of precisely intervening in RECK dysregulationfor the treatment of sepsis.

Sepsis, as a clinically critical disease, usually induces coagulation disorders. It has been reported that ERBB2 Interacting Protein (Erbin) is involved in the development of various inflammatory diseases, and macrophages are involved in the regulation of coagulation disorders in sepsis. However, the role of Erbin in coagulation disorders in sepsis and the relationship between Erbin and macrophage regulation of coagulation function are still unclear.

At the cellular level, macrophages were treated with lipopolysaccharide (LPS) or MEK inhibitor (PD98059), protein expression levels were detected by Western blot, co-immunoprecipitation (Co-IP), and immunofluorescence, mRNA expression levels were detected by quantitative real-time polymerase chain reaction (qPCR), and the concentration of tissue factor (TF) in cell supernatant was detected by enzyme linked immunosorbent assay (ELISA). At the animal level, the cecal ligation and perforation (CLP) model was constructed in mice, and the inflammatory response and coagulation disorder of mice were observed by hematoxylin-eosin (HE) staining, immunohistochemistry, ELISA, and automatic hemagglutination analyzer. The protein and mRNA expression level were detected by Western blot and qPCR. Pearson linear correlation analysis was used to analyze the correlation between the inflammation index and the coagulation function index.

We confirmed that the Erbin is involved in the regulation of coagulation function by macrophages and plays a role in the coagulation disorder of sepsis. In vivo studies have shown that mice with Erbin deletion have more obvious enhanced coagulation function, and in vitro studies have shown that Erbin knockout mediated macrophage secretion of TF by activating the Ras/Raf pathway.

Erbin reduces the coagulation activation by inhibiting TF release from macrophages.

Sepsis is associated with immune dysregulated and organ dysfunction due to severe infection. Clinicians aim to restore organ function, rather than prevent diseases that are prone to sepsis, resulting in high mortality and a heavy public health burden. Some chronic diseases can induce sepsis through inflammation cascade reaction and Cytokine Storm (CS). Interleukin (IL)-6, the core of CS, and its related signaling pathways have been considered as contributors to sepsis. Therefore, it is important to study the relationship between IL-6 and its related pathways in sepsis-related chronic diseases. This review generalized the mechanism of sepsis-related chronic diseases via IL-6 related pathways with the purpose to take rational management for these diseases. IL-6 related signaling pathways were sought in Kyoto Encyclopedia of Genes and Genomes (KEGG), and retrieved protein-protein interaction in the Search for Interaction Genes tool (STRING). In PubMed and Google Scholar, the studies were searched out, which correlating to IL-6 related pathways and associating with the pathological process of sepsis. Focused on the interactions of sepsis and IL-6 related pathways, some chronic diseases have been studied for association with sepsis, containing insulin resistance, Alcoholic liver disease (ALD), Alzheimer disease (AD), and atherosclerosis. This article summarized the inflammatory mechanisms of IL-6 cross-talked with other mediators of some chronic diseases in vitro, animal models, and human experiments, leading to the activation of pathways and accelerating the progression of sepsis. The clinicians should be highlight to this kind of diseases and more clinical trials are needed to provide more reliable theoretical basis for health policy formulation.

To determine the risk factors for poor prognosis of influenza-associated encephalopathy (IAE), 56 eligible children with IAE who were treated in the pediatric intensive care unit of Wuhan Children's Hospital from January 2022 to December 2023 were selected for retrospective analysis and grouped according to poor prognosis or not, and independent risk factors for poor prognosis were found by regression analysis. Results showed 26 children (26/30, 46.4%) had a poor prognosis. In the univariate analysis, the poor prognosis group compared with the clinically cured group showed a significant increase in the number of days of hospitalization (3.0 vs. 9.5 days, P < 0.001), high-sensitivity C-reactive protein (6.80 vs. 1.88 mg/L, P = 0.003), interleukin-6 (20.26 vs. 8.24 pg/mL, P = 0.001), interleukin-10 (11.75 vs. 4.72 pg/mL, P = 0.003), alanine aminotransferase (104.0 vs. 20.0 U/L, P = 0.011), aspartate azelotransferase (186.5 vs. 37.0 U/L, P = 0.003), serum albumin (37.99 vs. 40.76 g/L, P = 0.042), prothrombin time (13.2 vs. 11.4 s, P = 0.017), D-dimer (4.34 vs. 0.44 mg/L FEU, P < 0.001), peripheral blood CD19 B-cell count (35.11 vs. 32.75 cells/µL, P = 0.018), and cerebrospinal fluid chloride (126.82 vs. 125.50 mmol/L, P = 0.027) were statistically different in the above 11 indicators. After binary logistic regression analysis, it was concluded that D-dimer was an independent risk factor for poor prognosis (odds ratio = 1.440, 95% confidence interval 1.052-1.972, P = 0.023), and the area under the curve (95% confidence interval) was 0.802 (0.680-0.924), P < 0.001. When D-dimer was ≥ 1.18 mg/L FEU, the occurrence of poor prognosis was predicted with sensitivity and specificity of 65.4% and 96.7%, respectively. In conclusion, IAE has a high incidence of poor prognosis, in which D-dimer is a possible risk factor with discriminatory value in assessing the occurrence of poor prognosis. However, due to the limitations of retrospective single-center small sample size data, more confirmation from multicenter large sample size studies is needed in the future.

A 68-year-old Japanese man developed a fever, headache, hiccups, and altered consciousness. Brain magnetic resonance imaging revealed a hemorrhagic lesion in the right temporal lobe and multiple high-intensity white matter lesions. A brain biopsy showed pathological findings consistent with acute disseminated encephalomyelitis (ADEM), suggesting a diagnosis of acute hemorrhagic leukoencephalitis (AHLE), an aggressive ADEM variant. The patient also developed myodesopsia and was diagnosed with retinal vasculitis, likely due to a hyperimmune state caused by AHLE. Corticosteroids enabled full recovery. Although AHLE is uncommon in elderly individuals, clinicians should be aware of its occurrence in this patient subgroup and recognize potential retinal manifestations associated with AHLE.

Effective cancer therapies must address the tumor microenvironment (TME), a complex network of tumor cells and stromal components, including endothelial, immune, and mesenchymal cells. Durable outcomes require targeting both tumor cells and the TME while minimizing systemic toxicity. Interleukin-2 (IL-2)-based therapies have shown efficacy in cancers such as metastatic melanoma and renal cell carcinoma but are limited by severe side effects. Innovative IL-2-based immunotherapeutic approaches include immunotoxins, such as antibody-drug conjugates, immunocytokines, and antibody-cytokine fusion proteins that enhance tumor-specific delivery. These strategies activate cytotoxic CD8+ T lymphocytes and natural killer (NK) cells, eliciting a potent Th1-mediated anti-tumor response. Modified IL-2 variants with reduced Treg cell activity further improve specificity and reduce immunosuppression. Additionally, IL-2 conjugates with peptides or anti-angiogenic agents offer improved therapeutic profiles. Combining IL-2-based therapies with immune checkpoint inhibitors (ICIs), anti-angiogenic agents, or radiotherapy has demonstrated synergistic potential. Preclinical and clinical studies highlight reduced toxicity and enhanced anti-tumor efficacy, overcoming TME-driven immune suppression. These approaches mitigate the limitations of high-dose soluble IL-2 therapy, promoting immune activation and minimizing adverse effects. This review critically explores advances in IL-2-based therapies, focusing on immunotoxins, immunocytokines, and IL-2 derivatives. Emphasis is placed on their role in combination strategies, showcasing their potential to target the TME and improve clinical outcomes effectively. Also, the use of IL-2 immunocytokines in "in situ" vaccination to relieve the immunosuppression of the TME is discussed.

Clinical monitoring of pulmonary edema due to vascular hyperpermeability in acute respiratory distress syndrome (ARDS) poses significant clinical challenges. Presently, no biological or radiological markers are available for quantifying pulmonary edema. Our aim was to phenotype pulmonary edema and pulmonary vascular permeability in patients with coronavirus disease 2019 (COVID-19) ARDS. Transpulmonary thermodilution measurements were conducted in 65 patients with COVID-19 ARDS on the day of intubation to determine the extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPi). In parallel, ventilatory parameters, clinical outcomes, the volume of lung opacity measured by chest computed tomography (CT), radiographic assessment of lung edema (RALE) score by chest radiography, and plasma proteomics (358 unique proteins) were compared between tertiles based on the EVLWi and PVPi. Regression models were used to associate EVLWi and PVPi with plasma, radiological, and clinical parameters. Computational pathway analysis was performed on significant plasma proteins in the regression models. Patients with the highest EVLWi values at intubation exhibited poorer oxygenation parameters and more days on the ventilator. Extravascular lung water strongly correlated with the total volume of opacity observed on CT (r = 0.72, P < 0.001), whereas the PVPi had weaker associations with clinical and radiological parameters. Extravascular lung water did not correlate with the RALE score (r = 0.15, P = 0.33). Plasma protein concentrations demonstrated a stronger correlation with PVPi than with EVLWi. The highest tertile of PVPi was associated with proteins linked to the acute phase response (cytokine and chemokine signaling) and extracellular matrix turnover. In the clinical setting of COVID-19 ARDS, pulmonary edema (EVLWi) can be accurately quantified through chest CT and parallels deterioration in ventilatory parameters and clinical outcomes. Vascular permeability (PVPi) is strongly reflected by inflammatory plasma proteins.NEW & NOTEWORTHY This study is unique in that it phenotypes pulmonary edema in COVID-19 ARDS using various clinical parameters and biomarkers. First, there is a noteworthy tipping point in the amount of pulmonary edema at which ventilatory and clinical parameters deteriorate. Second, chest CT gives a good approximation of the amount of pulmonary edema. Finally, pulmonary vascular permeability is strongly reflected by inflammatory plasma proteins.

Interleukin-6 (IL-6) plays multifaceted roles in cancer and atherosclerosis. Initially recognized for its role in immune response and inflammation, IL-6 promotes tumor progression via the JAK-STAT and MAP kinase pathways and is associated with poor cancer prognoses. In atherosclerosis, IL-6 contributes to endothelial dysfunction and plaque formation. This review highlights the shared inflammatory mechanisms of IL-6 in both diseases and explores the regulatory dynamics of IL-6 signaling, including gene polymorphisms and epigenetic modifications.

Google Scholar, Scopus, and PubMed were searched for English-language articles on IL-6 and those reporting shared pathogenic mechanisms of IL-6 in cancer and atherosclerosis from their inception through June 2024.

The investigation into IL-6's mechanisms in cancer and atherosclerosis reveals the intricate and interconnected nature of inflammatory processes in chronic diseases. The role of IL-6 in both conditions underscores its centrality in disease pathology, particularly through its involvement in inflammation, immune modulation, and cellular proliferation. This commonality highlights IL-6 as a key player linking these seemingly distinct diseases.

Given the shared pathogenic mechanism of IL-6 in cancer and atherosclerosis, this narrative review concludes by emphasizing the therapeutic potential of modulating IL-6 in treating both cancer and atherosclerosis. It advocates for personalized treatment strategies that combine targeted therapies with lifestyle modifications. This holistic approach is considered crucial for effective disease management, given the diverse and complex roles IL-6 plays in these widespread conditions.

The COVID-19 outbreak has been declared the sixth Public Health Emergency of International Concern certified by the World Health Organization. With the extensive application of COVID-19 vaccines, rare but serious adverse reactions have gradually emerged, among which systemic capillary leak syndrome (SCLS) deserves our attention. SCLS is difficult to diagnose. Not only can it exacerbate various diseases, but also can lead to pulmonary edema, kidney failure, and even death. We summarized and discussed case reports of SCLS induced by COVID-19 vaccines to raise awareness of COVID-19 vaccine-associated rare diseases. We conducted a comprehensive search in Web of Science, PubMed and Embase and collected case reports of SCLS induced by COVID-19 vaccine before February 19, 2024. We identified and analyzed 12 articles, encompassing 15 cases. We synthesized the data to summerize possible mechanisms of SCLS, clinical manifestations, differential diagnoses, and therapeutic approaches. Most SCLS occurred after vaccination with the Pfe-Biontech mRNA vaccine (9/15) and following the second vaccination (10/15). Almost all patients experienced hypotension (13/15) and tachycardia (11/15). Most patients received intravenous fluids (9/15) and corticosteroids (9/15). 11 patients were recovered and were discharged, while 4 patients died. Inflammation and endothelial cell damage may be linked to SCLS and COVID-19 vaccines. These findings highlight the necessity of focusing on serious adverse reactions of COVID-19 vaccines and the urgency to reconsider the safety of COVID-19 vaccines.