Immune Cell Cytokine Research Articles

Immunomodulation via the Endocannabinoid System: Mechanisms and Therapeutic Potentials

The endocannabinoid system (ECS) plays a crucial role in regulating immune responses, influencing both innate and adaptive immunity through its interaction with cannabinoid receptors, particularly CB2, which is predominantly expressed on immune cells. This review explores the mechanisms of ECS-mediated immunomodulation, focusing on its ability to balance pro-inflammatory and anti-inflammatory processes, thereby contributing to immune homeostasis. Endocannabinoids, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), modulate immune cell activity, cytokine production, and migration. These actions make the ECS a promising therapeutic target for chronic inflammatory and autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. Additionally, the ECS has potential applications in cancer immunotherapy by modulating the tumor microenvironment and enhancing anti-tumor immune responses. Non-psychoactive cannabinoids like cannabidiol (CBD) have emerged as attractive candidates for therapeutic use, offering anti-inflammatory benefits without the adverse psychoactive effects associated with tetrahydrocannabinol (THC). However, challenges remain in understanding the ECS’s complex interactions within the immune system and optimizing cannabinoid-based therapies for clinical use. As research progresses, the ECS may provide novel therapeutic avenues for immune regulation and disease management, contributing to improved outcomes in a variety of immune-related disorders. Keywords: Endocannabinoid system, Immunomodulation, CB2 receptors, Inflammation, Autoimmune diseases

Depression decreases immunity and PD-L1 inhibitor efficacy via the hypothalamic–pituitary–adrenal (HPA) axis in triple-negative breast cancer

BackgroundDepression weakens antitumor immunity, yet the underlying mechanisms linking depression and tumor growth remain unclear. This study examines the influence of depression on the hypothalamic–pituitary–adrenal (HPA) axis, immunological function, and effectiveness of immunotherapy in triple-negative breast cancer (TNBC) patients. MethodsA mouse model of comorbid TNBC and depression was established via chronic restraint stress (CRS) and 4T1 tumor transplantation. A programmed cell death ligand 1 (PD-L1) inhibitor was used to manage mice with TNBC, and the ability of metyrapone to reverse the immune system changes induced by HPA axis activation in depression was evaluated. Mouse peripheral blood was used to measure HPA axis activity, immune cell numbers and cytokine levels. ResultsDepression activates the HPA axis, leading to increased levels of glucocorticoids. Depression led to an increase in the B-cell number and a reduction in the CD4+ T-cell and CD8+ T-cell numbers, without a statistically significant difference in the regulatory T (Treg) cell number. Furthermore, depression increased the levels of the cytokines interferon-gamma (IFN-γ), interleukin (IL)-1β, IL-4, IL-6, IL-8, and tumor necrosis factor (TNF)-α while decreasing the levels of IL-2 and IL-10. Similar results were observed in the context of PD-L1 inhibitor therapy. The depressed mice presented an increased tumor burden and a poor response to the PD-L1 inhibitor. The application of metyrapone during PD-L1 inhibitor treatment resulted in partial restoration of these depression-related alterations. ConclusionsDepression reduces the effectiveness of PD-L1 inhibitors by altering the number of immune cells and the levels of cytokines through activation of the HPA axis. Translational relevanceDepression is common in breast cancer patients and is associated with reduced antitumor immunity. There is limited knowledge regarding the specific mechanisms through which depression impairs antitumor immunity. Immunotherapy, which promotes the restoration of antitumor immunity, represents a promising treatment strategy for TNBC patients. However, the efficacy of immunotherapy can be compromised by depressive symptoms and the administration of glucocorticoids during treatment. It is still uncertain whether increasing glucocorticoid levels can reduce the efficacy of immunotherapy in patients with depression. The potential benefits of combining immunotherapy with glucocorticoid inhibitors compared with immunotherapy alone need to be evaluated for TNBC patients with concurrent depressive symptoms. Therefore, further clarification of the specific mechanisms by which depression impairs antitumor immunity is needed to inform future optimization of immunotherapy strategies.

Transcriptome combined with Mendelian randomization to screen key genes associated with mitochondrial and programmed cell death causally associated with diabetic retinopathy.

Mitochondrial dysfunction in the retina can induce apoptosis of retinal capillary cells, leading to diabetic retinopathy (DR). This study aimed to explore key genes related to programmed cell death (PCD) and mitochondria in DR via bioinformatic analysis. A differential analysis was performed to identify differentially expressed genes (DEGs) between DR and control samples using the GSE94019 dataset from the Gene Expression Omnibus (GEO) database. Pearson correlation analysis was then utilized to select genes linked to mitochondrial function and PCD (M-PCD). Candidate genes were identified by overlapping DR-DEGs and M-PCD genes, followed by functional annotation. Mendelian randomization (MR) analysis was employed to identify genes with causal relationships to DR. Key genes were identified through protein-protein interaction (PPI) analysis using six algorithms (DEgree, DMNC, EPC, MCC, Genes are BottleNeck, and MNC) within Cytoscape software. The expression patterns of these genes were validated using GSE94019 and GSE60436 datasets, as well as RT-qPCR. Enrichment analysis provided insights into the function and pathways of these key genes in DR. Differential immune cell profiles were determined via immune infiltration analysis, followed by exploring the relationships between immune cells, cytokines, and the identified genes. Correlations between key genes and apoptosis genes were also examined. In vivo experiments using RT-PCR, immunohistochemistry (IHC), and western blot analysis confirmed that MYC and SLC7A11 expression was significantly elevated in DR rat retinal tissues. From 658 candidate genes, 12 showed significant causal associations with DR. MYC and SLC7A11 were particularly notable, showing upregulated expression in DR samples and involvement in apoptosis and diabetes-related pathways. These genes were significantly associated with apoptotic genes and correlated positively with altered immune cell types and cytokines, suggesting a link between immune response and DR pathogenesis. In vivo findings confirmed that MYC and SLC7A11 expression was elevated in DR rat retinal tissues. Key genes (MYC and SLC7A11) associated with mitochondrial function and PCD in DR were identified, offering insights into DR's pathological mechanisms and potential targets for diagnostic and therapeutic strategies.

Differences in Plasma Extracellular Vesicles of Different Origin in On-Pump Versus Off-Pump Cardiac Surgery.

Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) causes a systemic inflammatory response that can worsen patient outcomes. Off-pump surgery has been associated with a reduced inflammatory response. The precise mechanisms and the role of extracellular vesicles (EVs) in this context are not fully understood. This study aimed to investigate the early immune response, including main T- and B-lymphocyte subsets, cytokine profiles, and plasma EVs, in patients undergoing off-pump (n = 18) and on-pump (n = 18) CABG. Thirty-six patients undergoing isolated CABG were enrolled in this randomized control study. Pre- and 24 h postoperative blood samples were analyzed for immune cell populations, cytokine levels, and plasma EV phenotyping. Off-pump CABG triggered a milder immune response than on-pump surgery. On-pump surgery led to greater changes in circulating EVs, particularly platelet- (CD62P+), endothelial- (CD31+), and B-cell-derived (CD19+), as well as platelet- and erythrocyte-derived aggregates (CD41+CD235a+). Levels of platelet-derived EVs, expressing both constitutional and activation markers (CD41+CD62P+) decreased in both groups of patients 24 h after surgery. On-pump cardiac procedures led to an increase in T-regulatory cell-derived EVs (CD73+CD39+), suggesting a potential mechanism for immune suppression compared to off-pump surgery. There were numerous correlations between EV levels and cytokine profiles following on-pump surgery, hinting at a close relationship. Leucocyte-derived EVs exhibited positive correlations with each other and with GRO but showed negative correlations with endothelial-derived EVs (CD90+ and CD31+). Additionally, CD73+ EVs demonstrated positive correlations with platelet counts and with erythrocyte-derived CD235a+ EVs. EV changes were significantly greater after on-pump surgery, highlighting a more pronounced response to this type of surgery and emphasizing the role of EVs as regulators of post-surgical inflammation.

Host genetics and gut microbiota influence lipid metabolism and inflammation: potential implications for ALS pathophysiology in SOD1G93A mice

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons, with genetic and environmental factors contributing to its complex pathogenesis. Dysregulated immune responses and altered energetic metabolism are key features, with emerging evidence implicating the gut microbiota (GM) in disease progression. We investigated the interplay among genetic background, GM composition, metabolism, and immune response in two distinct ALS mouse models: 129Sv_G93A and C57Ola_G93A, representing rapid and slow disease progression, respectively.Using 16 S rRNA sequencing and fecal metabolite analysis, we characterized the GM composition and metabolite profiles in non-transgenic (Ntg) and SOD1G93A mutant mice of both strains. Our results revealed strain-specific differences in GM composition and functions, particularly in the abundance of taxa belonging to Erysipelotrichaceae and the levels of short and medium-chain fatty acids in fecal samples. The SOD1 mutation induces significant shifts in GM colonization in both strains, with C57Ola_G93A mice showing changes resembling those in 129 Sv mice, potentially affecting disease pathogenesis. ALS symptom progression does not significantly alter microbiota composition, suggesting stability.Additionally, we assessed systemic immunity and inflammatory responses revealing strain-specific differences in immune cell populations and cytokine levels.Our findings underscore the substantial influence of genetic background on GM composition, metabolism, and immune response in ALS mouse models. These strain-specific variations may contribute to differences in disease susceptibility and progression rates. Further elucidating the mechanisms underlying these interactions could offer novel insights into ALS pathogenesis and potential therapeutic targets.

Increasing coil temperature of a third-generation e-cigarette device modulates C57BL/6 mouse lung immune cell composition and cytokine milieu independently of aerosol dose

ABSTRACT Higher coil temperature in e-cigarette devices increases the formation of aerosols and toxicants, such as carbonyls. At present, the health implications of vaping at higher temperatures, including exacerbation of pulmonary inflammation, are largely unknown when aerosol dose is considered. To isolate the pulmonary effects of coil temperature, C57BL/6 mice were exposed to e-cigarette aerosols generated at lower (190°C) or higher (250°C) temperature for 3 days, while maintaining a similar chamber aerosol concentration. Increasing coil temperature did not markedly alter aerosol mass-normalized emissions of select carbonyls formed from thermal degradation pathways including formaldehyde, acetaldehyde, propionaldehyde, and acetone under the tested environment. Total bronchoalveolar cells, primarily macrophages, were significantly decreased in mice exposed to aerosols generated with higher coil temperatures compared to lower temperature exposures. The gene expression of IFNβ, IL-1β, TNFα, and IL-10 in mouse lung tissue was significantly reduced following e-cigarette exposure under both conditions, compared to filtered air exposure. Higher temperature exposures further exacerbated downregulation of IFNβ and IL-1β. Data suggest that higher temperature vaping might modulate acute pulmonary immune responses, potentially inducing immune suppression, even when normalized for aerosol dose exposure. Coil temperature thus appears to be an important parameter that needs to be regulated to ensure harm reduction for e-cigarette users.

Mechanisms of Immune Evasion in PTEN Loss Prostate Cancer

PTEN (phosphatase and tensin homolog) is a frequently lost tumor suppressor gene in prostate cancer, leading to aggressive tumor behavior and poor clinical outcomes. PTEN loss results in aberrant activation of the PI3K/AKT/mTOR pathway, promoting oncogenesis. These alterations also lead to an immunosuppressive tumor microenvironment with altered immune cell infiltration, cytokine profiles, and immune checkpoint regulation. This review aims to provide a comprehensive overview of the mechanisms underlying PTEN loss in prostate cancer and the consequent immune alterations observed in this subtype, thus underscoring the importance of understanding PTEN-mediated immune modulation for the development of effective therapeutic interventions in prostate cancer.

Brain temperature, brain metabolites, and immune system phenotypes in temporal lobe epilepsy.

Epileptogenesis is linked to neuroinflammation. We hypothesized that local heat production caused by neuroinflammation can be visualized non-invasively invivo via brain magnetic resonance spectroscopic imaging (MRSI) and MRSI-thermometry (MRSI-t) and that there is a relationship in patients with temporal lobe epilepsy (TLE) between MRSI-t and brain metabolites choline and myo-inositol and between neuroimaging and cellular and serum biomarkers of inflammation. Thirty-six (36) participants, 18 with temporal lobe epilepsy (13 females) and 18 age-matched healthy controls (nine females), were enrolled prospectively and underwent MRSI/MRSI-t; TLE participants also provided blood samples. Temperature was measured using creatine as a reference metabolite. Analysis of Functional NeuroImages 3dttest++ tool was used to analyze voxel-level group differences in temperature, choline, and myo-inositol. Associations with immune cell subsets, cytokines, and chemokines related to inflammation were quantified using correlation coefficients with significant relationships as noted. Patients with TLE showed elevated temperature, choline, and myo-inositol in the temporal lobes. Higher brain temperature was associated with higher levels of cytokines and chemokines, including GM-CSF, TNF, IL-1β, and IL - 12p70, and lower frequency of immune cells including CD3+ T-cells, CD4+ T-cells, CD8+ T-cells, and classical monocytes. Higher choline was associated with higher levels of the cytokines including LT-α, IL-13, and IL-4, and higher myo-inositol was associated with a higher frequency of CD4+ T-cell and CD19+ B-cell subsets and higher levels of cytokines and chemokines including LT-α, IL-13, and CCL3. This study, for the first time, showed that in temporal lobes of patients with TLE temperature and metabolite changes correlate with cellular and serum biomarkers of inflammation. Our results provide support for further development of MRSI-t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool. Neuroinflammation is associated with excessive heat production which can be visualized with magnetic resonance spectroscopic imaging and thermometry (MRSI-t). We prospectively investigated the relationship between MRSI-t and cellular and serum measures of peripheral inflammation in patients with temporal lobe epilepsy (TLE); we compared the results of MRSI-t in patients with TLE to healthy controls. We showed a relationship between the temperature elevations in TLE and elevations of various measures of peripheral inflammation. Our results support further development of MRSI-t as a measure of neuroinflammation in epilepsy and potentially other neurological disorders and as an investigative and clinical tool.

Evaluation of the immune response of peripheral blood mononuclear cells cultured on Ti6Al4V-ELI polished or etched surfaces.

While titanium and its alloys exhibit excellent biocompatibility and corrosion resistance, their polished surfaces can hinder fast and effective osseointegration and other biological processes, such as angiogenesis, due to their inert and hydrophobic properties. Despite being commonly used for orthopedic implants, research focuses on developing surface treatments to improve osseointegration, promoting cell adhesion and proliferation, as well as increasing protein adsorption capacity. This study explores a chemical treatment intended for titanium-based implants that enhances tissue integration without compromising the mechanical properties of the Ti6Al4V substrate. However, recognizing that inflammation contributes to nearly half of early implant failures, we assessed the impact of this treatment on T-cell viability, cytokine production, and phenotype. Ti6Al4V with extra low interstitial (ELI) content discs were treated with hydrofluoric acid followed by a controlled oxidation step in hydrogen peroxide that creates a complex surface topography with micro- and nano-texture and modifies the chemistry of the surface oxide layer. The acid etched surface contains an abundance of hydroxyl groups, crucial for promoting bone growth and apatite precipitation, while also enabling further functionalization with biomolecules. While cell viability remained high in both groups, untreated discs triggered an increase in Th2 cells and a decrease of the Th17 subset. Furthermore, peripheral blood mononuclear cells exposed to untreated discs displayed a rise in various pro-inflammatory and anti-inflammatory cytokines compared to the control and treated groups. Conversely, the treated discs showed a similar profile to the control, both in terms of immune cell subset frequencies and cytokine secretion. The dysregulation of the cytokine profile upon contact with untreated Ti6Al4V-ELI discs, namely upregulation of IL-2 could be responsible for the decrease in Th17 frequency, and thus might contribute to implant-associated bacterial infection. Interestingly, the chemical treatment restores the immune response to levels comparable to the control condition, suggesting the treatment's potential to mitigate inflammation by enhancing biocompatibility.

Investigation of the impact of magnetic resonance imaging-assisted surgery on immune cell cytokine levels and efficacy in patients with gliomas

Objectivethis work was to investigate the impact of magnetic resonance imaging (MRI)-assisted surgery on immune cell factors and surgical efficacy in glioma patients, aiming to deepen understanding of surgical effects on immune status and provide evidence for clinical strategies. Materials and Methodsa retrospective analysis of 120 patients treated at Qianjiang Hospital from January 2022 to December 2023 was conducted. Patients underwent traditional craniotomy (control group, CG) or MRI-assisted stereotactic minimally invasive surgery (research group, RG). Immune cell factors, treatment outcomes, cognitive function, daily activities, and adverse reactions (ARs) were compared. Resultspostoperatively, arginine vasopressin (AVP) and β-endorphin (β-EP) levels decreased in both groups, more so in CG (P<0.05). Helper T cell 1 (Th1) levels increased in both, more in controls, while Th2 and Th17 decreased, more in CG (P<0.05). Glasgow coma scale (GCS) scores increased more in the RG, National Institutes of Health Stroke Scale (NIHSS) scores decreased more (P<0.05), and activities of daily living (ADL) scores increased more in the RG (P<0.05). The RG had more effective treatments and fewer ineffective outcomes (P<0.05), and fewer recurrences, metastases, and ARs (P<0.05). ConclusionMRI-assisted surgery enhances immune factors, functional abilities, and shows efficacy with fewer ARs, indicating its clinical value.

Aspartyl proteases target host actin nucleator complex protein to limit epithelial innate immunity

Epithelial-immune cell communication is pivotal to control microbial infections. We show that glycosylphosphatidylinositol-linked aspartyl proteases (Yapsins) of the human opportunistic pathogenic yeast Candida glabrata (Cg) thwart epithelial cell (EC)-neutrophil signalling by targeting the EC protein, Arpc1B (actin nucleator Arp2/3 complex subunit), which leads to actin disassembly and impeded IL-8 secretion by ECs. Further, the diminished IL-8 secretion inhibits neutrophil migration, and protects Cg from the neutrophil-mediated killing. CgYapsin-dependent Arpc1B degradation requires Arginine-142 in Arpc1B, and leads to reduced Arpc1B-p38 MAPK interaction and downregulated p38 signalling. Consistently, Arpc1B or p38 deletion promotes survival of the Cg aspartyl protease-deficient mutant in ECs. Importantly, kidneys of the protease-deficient mutant-infected mice display elevated immune cell infiltration and cytokine secretion, implicating CgYapsins in immune response suppression in vivo. Besides delineating Cg-EC interplay, our results uncover a novel target, Arpc1B, that pathogens attack to constrain the host signalling networks, and link Arpc1B mechanistically with p38 activation.

WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD.

Recent advancements highlight the intricate interplay between the extracellular matrix (ECM) and immune responses, notably in respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). The ECM, a dynamic structural framework within tissues, orches-trates a plethora of cellular processes, including immune cell behavior and tissue repair mecha-nisms. WNT1-inducible-signaling pathway protein 1 (WISP1), a key ECM regulator, controls immune cell behavior, cytokine production, and tissue repair by modulating integrins, PI3K, Akt, β-catenin, and mTOR signaling pathways. WISP1 also induces macrophage migration inhibitory factor (MIF) expression via Src kinases and epidermal growth factor receptor (EGFR) activation. MIF, through its wide range of activities, enhances inflammation and tissue restructuring. Rec-ognized for its versatile roles in regulating the immune system, MIF interacts with multiple immune components, such as the NLRP3 inflammasome, thereby sustaining inflammatory pro-cesses. The WISP1-MIF axis potentially unveils complex molecular mechanisms governing im-mune responses and inflammation. Understanding the intricate roles of WISP1 and MIF in the pathogenesis of chronic respiratory diseases such as asthma and COPD could lead to the identi-fication of novel targets for therapeutic intervention to alleviate disease severity and enhance patient outcomes.

Intestinal and hepatic benefits of BBR-EVO on DSS-induced experimental colitis in mice.

Ulcerative colitis (UC), characterized by disrupted intestinal barrier integrity and chronic inflammation, was modeled in mice via dextran sulfate sodium (DSS) induction. This study explored the therapeutic potential of berberine-evodiamine (BBR-EVO), bioactive components of the traditional Chinese medicine Yulian decoction, in DSS colitis. BBR-EVO intervention ameliorated weight loss, diarrhea, colonic shortening, and histopathological damage in colitic mice. The substance increased antioxidant activity while reducing high levels of pro-inflammatory cytokines in the colon, including as TNF-α, IL-1β, and IL-6. BBR-EVO inhibited the DSS-induced decrease in the tight junction proteins ZO-1 and occludin, according to immunohistochemistry. 16S rRNA sequencing demonstrated BBR-EVO partially attenuated DSS-elicited intestinal dysbiosis, reducing opportunistic pathogens and restoring diminished beneficial taxa. Critically, BBR-EVO alleviated secondary hepatic injury in colitic mice, mitigating immune cell infiltration, oxidative stress, cytokine production, and ultrastructural damage, likely by beneficially modulating gut-liver crosstalk. This study reveals BBR-EVO, derived from a traditional Chinese medicine, confers multi-target protective effects in experimental colitis and associated hepatic pathology, warranting further evaluation as a potential therapy for inflammatory bowel diseases like UC. The mechanisms may involve simultaneous augmentation of intestinal barrier integrity, inhibition of inflammation, microbiota regulation, and gut-liver axis optimization.

Nasally delivered chitosan-coated poly(lactide-co-glycolide) encapsulating honeybee venom enhances T helper 1-related immunity against Salmonella Typhimurium infection in pigs.

Salmonella Typhimurium is a significant zoonotic concern for human food poisoning and a substantial economic burden in the swine industry. We previously reported that nasally delivered chitosan-coated poly(lactide-co-glycolide) (PLGA) encapsulating honeybee venom (CP-HBV) could enhance CD4+ T helper 1 (Th1)-related immune responses in healthy pigs. Building upon these findings, the current study aimed to investigate the protective immune enhancement by nasally delivered CP-HBV in pigs challenged with S Typhimurium. 36 healthy, 4-week-old, female, Landrace X Yorkshire X Duroc pigs. 36 pigs were allocated into 3 groups: CP-HBV (n = 16), control (n = 16), and healthy baseline control (n = 4). CP-HBV and control groups were challenged with S Typhimurium 7 days post-treatment. Pigs from the healthy control group were sacrificed at 0 days postinfection (DPI), and 4 pigs from each of the control and CP-HBV groups were sacrificed at 1, 2, 4, and 7 DPI. Salmonella shedding, immune cell frequencies, cytokines, and transcriptional factor expression levels were measured. The CP-HBV group exhibited lower bacterial shedding and an enhanced Th1-related immune response characterized by an upregulation of CD4+ T cells and CD4+ Interferon-γ+ T cells, accompanied by increased expression of Th1-related cytokines and reduced expression of regulatory T cells and immunosuppressive cytokines compared to the control group. CP-HBV is a promising strategy for controlling Salmonella infections in pigs and improving public health.

Sepsis induced dysfunction of liver type 1 innate lymphoid cells

BackgroundSepsis is a life-threatening condition triggered by uncontrolled immune responses to infection, leading to widespread inflammation, tissue damage, organ dysfunction, and potentially death. The liver plays a crucial role in the immune response during sepsis, serving as a major site for immune cell activation and cytokine production. Liver type 1 innate lymphoid cells (ILCs) consist of NK cells and ILC1s. They maintain the local immune microenvironment by directly eliminating target cells and secreting cytokines. However, the specific roles and pathological changes of liver-resident NK cells and ILC1s during sepsis remain poorly understood.ResultsThis study aims to investigate the pathological changes of NK cells and ILC1s, which might contribute the dysfunction of liver. Sepsis mouse model was established by cecal ligation and puncture (CLP). Mouse immune cells from liver were isolated, and the surface makers, gene expression profiles, cytokine response and secretion, and mitochondrial function of NK (Natural Killer) cells and ILC1s (Innate Lymphoid Cell 1) were analyzed. A significant decrease in the number of mature NK cells was observed in the liver after CLP. Furthermore, the secretion of interferon-gamma (IFN-γ) was found to be reduced in spleen and liver NK cells when stimulated by IL-18. Mitochondrial activities in both liver NK cells and ILC1 were found to be increased during sepsis, suggesting an enhanced metabolic response in these cells to combat the infection. However, despite this heightened activity, liver NK cells exhibited a decreased level of cytotoxicity, which might impact their ability to target infected cells effectively. RNA sequencing supported and provided the potential mechanisms for the proinflammatory effects and exhaustion like phenotypes of liver NK cells.ConclusionsSepsis induces dysfunction and exhaustion-like phenotypes in liver NK cells and ILC1, which might further impair other immune cells and represent a potential therapeutic target for sepsis.

Role of Dysregulated Immune Biomarkers in Hepatocellular Carcinoma Metastasis: A Systematic Meta-Analysis Review

The liver plays a crucial role in immune system regulation, but dysregulation of immunological networks contributes to chronic liver diseases like hepatocellular carcinoma. This malignant tumor is the third leading cause of cancer death. An imbalanced immune system, characterized by alterations in immune cell count, cytokine levels, and inhibitory receptors, can impact metastasis by suppressing the immune system's ability to fight cancer cells. This study aims to investigate the potential biomarkers playing a crucial role in immune dysregulation resulting in hepatocellular carcinoma metastasis. A comprehensive and systematic literature review was conducted using both free words and search terms. The data extraction was then performed by a thorough literature screening. Next, the meta-analysis was performed using the metabin function of the meta library in R to evaluate the patient cases reporting metastasis in the event group. A total of 1,008 cases were considered, with 357 as events and 651 as nonevents. The results of the meta-analysis demonstrated the significant role of biomarkers in immune dysregulation causing metastasis (risk ratio = 0.54, 95% confidence interval: 0.4972, 0.6048, I 2 = 92.4%, p &lt; 0.01). In addition to the immune dysregulation explored in this study, the impact of tumor size on hepatocellular carcinoma progression and metastasis is a crucial consideration. A notable difference of 41 more cases was reported for larger tumor sizes. The study integrates immune dysregulation biomarkers and tumor size factors influencing hepatocellular carcinoma metastasis, offering valuable insights for future research and therapeutic interventions for improved clinical outcomes.

Vortioxetine ameliorates experimental autoimmune encephalomyelitis model of multiple sclerosis in mice via activation of PI3K/Akt/CREB/BDNF cascade and modulation of serotonergic pathway signaling

Multiple sclerosis (MS) is a chronic condition characterized by immune cell infiltration and cytokine overproduction that led to myelin sheath inflammatory assaults, thus causing axonal destruction. The former consequently provokes motor impairment and psychological disorders. Markedly, depression is one of the most prevalent lifelong comorbidities that negatively impacts the quality of life in MS patients. Vortioxetine (VTX), a multi-modal molecule prescribed to manage depression and anxiety disorder, additionally, it displays a promising neuroprotective properties against neurodegenerative diseases such as Alzheimer's and Parkinson's. To this end, the present study investigated the potential therapeutic efficacy of VTX against experimental autoimmune encephalomyelitis (EAE) model of MS in mice.Notably, treatment with VTX significantly ameliorated EAE-induced motor disability, as evident by enhanced performance in open field, rotarod and grip strength tests, alongside a reduction in immobility time during the forced swimming test, indicating a mitigation of the depressive-like behavior; outcomes that were corroborated with histological examinations and biochemical analyses. Mechanistically, VTX enhanced serotonin levels by inhibiting both serotonin transporter (SERT) and indoleamine 2,3-dioxygenase (IDO) enzyme, thereby promoting the activation of serotonin 1A (5-HT1A) receptor. The latter triggered the stimulation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) cascade that entailed activation/phosphorylation of cAMP response element-binding protein (CREB). This activation increased brain derived neurotrophic factor (BDNF) and myelin basic protein (MBP) contents that mitigated demyelination in the corpus callosum. Furthermore, VTX suppressed phospho serine 536 nuclear factor kappa B (pS536 NF-κB p65) activity and reduced tumor necrosis factor-alpha (TNF-α) production. The results underscore VTX's beneficial effects on disease severity in EAE model of MS in mice by amending both inflammatory and neurodegenerative components of MS progression.

Possible immune mechanisms of gut microbiota and its metabolites in the occurrence and development of immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and impaired production, leading to an elevated bleeding tendency. Recent studies have demonstrated an important link between the gut microbiota and the onset and progression of several immune diseases in humans, emphasizing that gut microbiota-derived metabolites play a non-negligible role in autoimmune diseases. The gut microbiota and its metabolites, such as short-chain fatty acids, oxidized trimethylamine, tryptophan metabolites, secondary bile acids and lipopolysaccharides, can alter intestinal barrier permeability by modulating immune cell differentiation and cytokine secretion, which in turn affects the systemic immune function of the host. It is therefore reasonable to hypothesize that ecological dysregulation of the gut microbiota may be an entirely new factor in the triggering of ITP. This article reviews the potential immune-related mechanisms of the gut microbiota and representative metabolites in ITP, as well as the important influence of leaky gut on the development of ITP, with a view to enriching the theoretical system of ITP-related gut microecology and providing new ideas for the study of ITP.

Interleukin-17F suppressed colon cancer by enhancing caspase 4 mediated pyroptosis of endothelial cells

The combination of anti-angiogenic treatment and immunotherapy presents a promising strategy against colon cancer. Interleukin-17F (IL-17F) emerges as a critical immune cell cytokine expressed in colonic epithelial cells, demonstrating potential in inhibiting angiogenesis. In order to clarify the roles of IL-17F in the colon cancer microenvironment and elucidate its mechanism, we established a mouse colon carcinoma cell line CT26 overexpressing IL-17F and transplanted it subcutaneously into syngeneic BALB/c mice. We also analyzed induced colon tumor in IL-17F knockout and wild type mice. Our results demonstrated that IL-17F could suppress colon tumor growth in vivo with inhibited angiogenesis and enhanced recruitment of cysteine-cysteine motif chemokine receptor 6 (CCR6) positive immune cells. Additionally, IL-17F suppressed the tube formation, cell growth and migration of endothelial cells EOMA in vitro. Comprehensive bioinformatics analysis of transcriptome profiles between EOMA cells and those treated with three different concentrations of IL-17F identified 109 differentially expressed genes. Notably, a potential new target, Caspase 4, showed increased expressions after IL-17F treatment in endothelial cells. Further molecular validation revealed a novel downstream signaling for IL-17F: IL-17F enhanced Caspase 4/GSDMD signaling of endothelial cells, CT26 cells and CT26 transplanted tumors, while IL-17F knockout colon tumors exhibited decreased Caspase 4/GSDMD signaling. The heightened expression of the GSDMD N-terminus, coupled with increased cellular propidium iodide (PI) uptake and lactate dehydrogenase (LDH) release, revealed that IL-17F promoted pyroptosis of endothelial cells. Altogether, IL-17F could modulate the colon tumor microenvironment with inhibited angiogenesis, underscoring its potential as a therapeutic target for colon cancer.

AYA22A Aptamers Mitigate Peanut Allergenicity: Insights from Degranulation Assays and Modulating Immune Responses

Food allergy, particularly peanut allergy (PA), is a growing health concern affecting millions globally. PA can lead to severe reactions, including fatal anaphylaxis. Despite the availability of FDA-approved therapies like Palforzia, a cure remains elusive. Current immunotherapies show promise but lack a definitive cure. This study applies an established computational biology tool to design aptamers targeting Ara h1 and Ara h2. The in silico design aims to streamline the selection process, enabling cost-effective and rapid identification of aptamer candidates. The developed aptamers (AYA22A, including AYA22AR321, AYA22AR211, and AYA22AR524), demonstrated efficacy in inhibiting degranulation of RBL-2H3 cells (rat basophilic leukemia cell line) in vitro. They showed promise in neutralizing peanut allergen-induced immune responses. The selected aptamers inhibited degranulation in RBL-2H3 cells, addressing concerns in raw peanuts. Moreover, these aptamers demonstrated stability and effectiveness in peanut plant seeds and commercial products. Our aptamers exhibited potential in modulating immune responses associated with peanut allergy. They influenced Th1/Th2 balance, indicating a role in cytokine regulation. In vitro studies also showed the aptamers’ impact on immune cell expression and cytokine production, resembling responses observed with established immunotherapies. The findings suggest AYA22A aptamers as a potential therapeutic option for peanut allergy, providing a basis for further in vivo investigations.