Higher Levels Of TNF-α Research Articles

Influence of intestinal permeability and endotoxinemia on the course of asthma in obese patients

Objective. To study the characteristics of asthma with a severe course in obese patients and to evaluate the relationship of the level of intestinal endotoxin (ET) and fecal zonulin with clinical, laboratory and instrumental indicators in such patients. Materials and methods. The study included 98 patients with asthma combined with obesity (group 1 – mild asthma (n = 47), group 2 – severe asthma (n = 51)) and 45 obese patients without asthma composed the comparison group. A complete standard examination and tests were conducted in all the patients. Intestinal ET, fecal zonulin, TNF-a, IFN-g, IL-4, 6, 10, 17, total IgE levels were assessed as well. The IBM SPSS Statistics 26.0 application software package was used for statistical calculations. The results were considered as statistically significant at the level of p 0,05. Results. In patients of both groups, the average age of onset was 43 years. The median duration of BA characteristics was higher in patients of group 2: 14 [10; 19] years (p = 0.013). In all groups, CRPhs values increased significantly and the highest ones were in patients with severe asthma (p 0.001). Significantly lower levels of FVC, FEV1, FEV1/FVC, IL-10 (p0.001) with uncontrolled course of asthma (p = 0.008) and rare control (p = 0.009) occurred in patients of group 2. Higher levels of TNF-a, IFN-g, IL-6,17, intestinal ET, fecal zonulin were revealed in patients of group 2 (p≤0.001). The level of fecal zonulin positively correlated with the level of intestinal ET in patients of group 2 (p0.001, rs=0.813). In patients of group 2 direct correlations of the fecal zonulin and intestinal ET with BMI, WC, HC, WC/HC, lack of BA control, CRPhs, TNF-a, IL-6,17, IFN-g, LDL were established and inverse correlations were with IL-10, HDL, FEV1, AST; a negative correlation of fecal zonulin levels with FVC was also revealed. Conclusions. The obtained results allow us to speak about the existence of a clinical complex “severe asthma – obesity – intestinal endotoxemia and increased intestinal permeability” which is characterized by the predominance of pro-inflammatory markers, increased levels of intestinal ET and fecal zonulin, reduced function of external breathing.

Deoxynivalenol induces ovarian damage and uterine changes in prepubertal and adult mice

Deoxynivalenol (DON) is associated with reproductive toxicity in animals. The frequent contamination of cereal-based foods with DON and the high intake of these by children raises particular concern about the susceptibility of this subpopulation to adverse effects from this mycotoxin. However, age-related differences in the in vivo reproductive toxicity of DON have not been evaluated. Therefore, the effects of DON on serum follicle-stimulating hormone (FSH) levels, histology, and inflammatory and oxidative stress responses in the ovaries and uteruses of prepubertal and adult mice were investigated. Twenty female prepubertal Swiss mice (21 days old) and 20 young adult mice (65 days old) were fed a control diet or a diet containing 10 mg of DON/kg of feed for 15 days (prepubertal mice) and 28 days (adult mice). In the ovaries, DON induced an increase in the lesional score in both age groups. Ingestion of DON decreased FSH levels in prepubertal females, whereas an increase was observed in adult mice. In prepubertal mice, a reduction in the number of macrophages and increased levels of TNF-α were observed in the ovaries of the DON group, while in adult animals, an increase in the number of macrophages and higher levels of TNF-α were noted. The prepubertal animals showed edema in the uterine tissue and increased thickness of the uterine wall and endometrium. Exposure to DON led to an increase in type I collagen in the uteruses of adult mice, while in prepubertal mice, a decrease in type III collagen was observed. DON exposure also resulted in a decrease in FRAP levels and an increase in ABTS and lipid peroxidation in the uteruses of prepubertal mice. Taken together, the results indicate that the effects of DON on reproductive organs are age-specific, with toxicity established as early as the prepubertal period.

Induced collagen type-I secretion by hepatocytes of the melanoma liver metastasis is associated with a reduction in tumour-infiltrating lymphocytes.

Overall patients with melanoma liver metastasis (MLiM) have a dismal prognosis and poor responses to the standard of care treatment. Understanding the role of the tumour microenvironment (TME) is critical for discovering better strategies to overcome intrinsic therapy resistance in MLiM. The aim was to understand the crosstalk signalling pathways between hepatocytes and metastatic melanoma cells in the TME of MLiM. Hepatocytes and melanoma tumour cells of MLiM were assessed using transcriptomic NanoString GeoMx digital spatial profiling (NGDSP) assay. Functional assays were performed using normal hepatocytes and MLiM-derived cell lines. Validation was performed using multiplex immunofluorescence. In NGDSP analysis adjacent normal hepatocytes (ANH) had higher CXCR4 and COL1A1/2 levels than distant normal hepatocytes (DNH), while melanoma cells had higher TNF-α levels. In vitro, MLiM cell lines released TNF-α which upregulated CXCR4 and CXCL12 levels in ANH. CXCL12 activated CXCR4, which triggered AKT and NFκB signalling pathways. Consequently, AKT signalling induced the upregulation of collagen type I. MLiM were significantly encircled by a shield of collagen, whereas other liver metastases showed reduced levels of collagen. Of all the liver metastasis analyzed, the presence of collagen in melanoma liver metastasis was associated with a reduction in tumour-infiltrating lymphocytes. MLiM modified ANH to increase collagen production and created a physical barrier. The collagen barrier was associated with a reduction of immune cell infiltration which could potentially deter MLiM immune surveillance and treatment responses. Spatial analyses of melanoma liver metastasis show that adjacent normal hepatocytes have increased collagen-type I levels. Melanoma liver metastases tumour cells secrete enhanced levels of TNF-α to stimulate CXCR4/CXCL12 upregulation in adjacent normal hepatocytes. Activation of CXCR4 promotes AKT and NF-κB signalling pathways to promote collagen-type I secretion in adjacent normal hepatocytes. Elevated collagen levels were associated with reduced tumour-infiltrating lymphocytes.

Adiponectin and Inflammatory Marker Levels in the Elderly Patients with Diabetes, Mild Cognitive Impairment and Depressive Symptoms.

Some studies suggest that low-grade inflammation and adipokines may be involved in mild cognitive impairment (MCI) and depression in subjects with type 2 diabetes; however, the available data concerning the elderly population are limited. Therefore, we conducted novel research to determine the serum adiponectin, hs-CRP and TNF-α levels in elderly diabetic patients with MCI and depressive symptoms and to identify the factors associated with MCI in this group. A total of 178 diabetic patients (mean age 84.4 ± 3.4 years) were screened for MCI and depressive symptoms. Various biochemical and biomarker data were collected. We found that patients with MCI and depressive symptoms demonstrated lower adiponectin levels and high hs-CRP and TNF-α. In this group, adiponectin concentration was negatively correlated with hs-CRP, TNF-α, HbA1c, and GDS-30 scores and positively correlated with MoCA scores. Multivariable analysis found the risk of MCI to be associated with higher TNF-α levels, fewer years of formal education, an increased number of comorbidities, and the presence of CVD. We concluded that low-grade inflammation and the presence of adipokines are associated with MCI and depressive symptoms in elderly diabetics. Further research should evaluate the suitability of Hs-CRP, TNF-α, and adiponectin as diagnostic markers for MCI and potential therapeutic targets.

Electroacupuncture attenuates depressive-like behaviors in poststroke depression mice through promoting hippocampal neurogenesis and inhibiting TLR4/NF-κB/NLRP3 signaling pathway.

The aim of this study was to investigate the impact and underlying molecular mechanisms of electroacupuncture on mice with poststroke depression (PSD). Mice were randomly allocated into sham, PSD, and electroacupuncture groups. Mice in the PSD and electroacupuncture groups underwent middle cerebral artery occlusion (MCAO) surgery following with sedentary behavior. Electroacupuncture targeting Zusanli (ST36) acupoint was performed 24 h after MCAO for 4 weeks in electroacupuncture group. The sucrose preference test, forced swimming test, open field test, tail suspension test, elevated plus maze, Catwalk analysis, RNA sequencing, Nissl staining, Golgi staining, TUNEL staining, Edu labeling, and doublecortin staining were performed. Lymphocyte subsets in peripheral blood and the levels of IL-1β, IL-6, TNF-α, and expression of Iba1/CD86, Iba1/NLRP3, TLR4/p38/NF-κB/NLRP3 pathways in the hippocampus were detected. Electroacupuncture effectively protected against the development of depression-like symptoms. The number of granulosa cells and doublecortin-positive cells in the dentate gyrus (DG) were significantly decreased in PSD group, which were significantly upregulated ( P < 0.01) by electroacupuncture. Electroacupuncture also significantly reduced ( P < 0.05) TUNEL-positive cells in the DG and CA1. RNA-seq revealed that electroacupuncture may exert antidepressant effect by regulating the inflammation mediated by TLR4/NF-κB/NLRP3 pathway in hippocampus. Electroacupuncture remarkably elevated ( P < 0.01) the ratio of CD4+ to CD8+ T cells and percentage of CD3-CD49b+ cells in CD45+CD49b+ cells in the peripheral blood. Electroacupuncture significantly reduced ( P < 0.05) the high levels of IL-1β, IL-6, TNF-α, iba1, TLR4, p-p38, p-NF-κB, and NLRP3 and sedentary behavior. Electroacupuncture was observed to mitigate depression symptoms and increase hippocampal neurogenesis in mice with PSD, possibly by inhibiting TLR4/p38/NF-κB/NLRP3 pathways and improving the microglia-mediated inflammatory microenvironment in the hippocampus.

Oocyte donation pregnancies with high fetal-maternal immunogenetic dissimilarity show alterations in the maternal peripheral immunoregulatory response

Oocyte donation (OD) pregnancies result in increased fetal-maternal immunogenetic dissimilarity due to paternal and donor-derived genes. Higher fetal-maternal HLA mismatches are correlated with preeclampsia. Therefore, this study explored the maternal immune response, focusing on regulatory T cells (Tregs), during low versus high allogeneic pregnancies, and healthy versus preeclamptic OD pregnancies. Ten healthy and five preeclamptic OD pregnancies were included. Maternal peripheral blood was collected at different stages of pregnancy. Fetal-maternal HLA mismatches were determined, and immunophenotyping of peripheral blood mononuclear cells was conducted using a 22-colour spectral flow cytometry panel. Cytokines and hormones were detected in maternal plasma using ELISA and Luminex assays. The findings show similarities, but also distinct differences between low and high allogeneic healthy OD pregnancies. Early high allogeneic OD pregnancy showed reduction in Tregs, and CD8+ T cells, alongside lower percentage of effector/memory Tregs expressing PD-1 and Helios. Additionally, high allogeneic OD pregnancies showed increased IL-6 and progesterone in the first trimester. These variations suggest a different mode of immune regulation in early high allogeneic OD pregnancies, possibly to maintain healthy pregnancy. Further comparative analyses revealed reduced CD45RO+CTLA-4+ Tregs and increased latent TGF-β1 and -β2 levels in early preeclamptic compared to healthy OD pregnancy. Late-stage preeclamptic OD pregnancies exhibited higher frequencies of CD45RO+TIGIT+ Tregs and higher levels of TNFα, indicating both a regulatory and pro-inflammatory environment. Overall, this study sheds light on the course of various immunoregulatory key players in OD pregnancy, and expands knowledge on maternal tolerance in this particular type of pregnancy.

Differential plasma cytokine variation following X-ray or proton brain irradiation using machine-learning approaches

PurposeX-ray and proton irradiation have been reported to induce distinct modifications in cytokine expression in vitro and in vivo, suggesting a dissimilar inflammatory response between X-rays and protons. We aimed to investigate the differences in cytokine profiles early following fractionated brain irradiation with X-rays or protons and their relationship with leukocyte subpopulations in rodents. Materials and methodsOur study utilized data from 80 tumor-free mice subjected to X-ray or proton brain irradiation in four fractions of 2.5Gy. Sixteen non-irradiated mice were used as the controls. Blood was collected 12h postirradiation to examine the profile of 13 cytokines. Correlation analysis, principal component analysis (PCA), and tree-based modeling were used to investigate the relationship between cytokine levels and leukocyte subpopulation variations following irradiation in the blood. ResultsRegardless of the irradiation type, brain irradiation resulted in a notable elevation in the plasma levels of IFN-γ and MCP-1. The use of either X-ray or proton beam had differential effect on plasma cytokine levels following brain irradiation. Specifically, X-ray irradiation was associated with significantly increased plasma levels of IFN-β, IL-12p70, and IL-23, along with a decreased level of IL-1α, in comparison to proton irradiation. Correlation analysis revealed distinct cytokine regulatory patterns between X-ray and proton brain irradiation. PCA highlighted the association of MCP-1, IL-6, TNF-α, IL-17A, and IFN-γ with neutrophils, monocytes, and naïve T-cells following X-ray irradiation. TNF-α and IL-23 levels correlated with naïve CD4+-cells following proton irradiation. Tree-based models demonstrated that high TNF-α level resulted in an increase in naïve T-cells, neutrophils, and monocytes, whereas low IL-6 level was associated with decreases in these cell counts. ConclusionOur findings revealed distinct inflammatory responses induced by X-ray irradiation in contrast to proton brain irradiation, as demonstrated by the differential regulation of cytokines in the bloodstream. Moreover, the study highlighted the association between specific cytokine levels and various leukocyte subpopulations. Further investigation is essential to accurately determine the impact of proton and X-ray brain irradiation on the inflammatory response and the efficacy of radiotherapy treatment.

Measuring the Concentration of Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α) in People infected with Cutaneous leishmaniasis in Tikrit

The study conducted in Salahaddeen Governorate aimed to measure the concentrations of cytokines (interleukin-6 and tumor necrosis factor-alpha) in patients infected with Baghdad boil and to compare these concentrations with those of the control group. The endemic disease of leishmaniasis manifests in three types in Iraq; cutaneous, mucocutaneous and visceral. The most common type is cutaneous leishmaniasis (CL) which causes skin sores. CL attributed to L. tropica is disseminated via the bite of an infected female sand fly. The study was conducted at Salahaddeen Teaching Hospital in Salahaddeen Governorate, Iraq, from March 1, 2021, to September 1, 2022. Detailed data were collected about age, gender, residence, location, number and type of lesions (wet or dry). Sixty clinical cases of cutaneous leishmaniasis were included in the study. The cytokine concentration of interleukin-6 (IL-6) exhibited an increase, reaching 94.7a±7.74 picograms/ml in patients infected with multiple leishmaniasis lesions (7-10 lesions). Conversely, the lowest concentration was observed at 56.3b±7.43 picograms/ml in patients with 1-3 lesions. Furthermore, the concentration of interleukin-6 reached its peak in patients with dry lesions (96.0a±10.9) compared to those with wet lesions (63.3b±12.4). An elevation in tumor necrosis factor (TNF-α) levels was observed across different age groups, with patients infected with cutaneous leishmaniasis typically falling within the age range of 11 to 40. Consistently, the highest TNF-α levels were documented annually in patients with cutaneous leishmaniasis, specifically within the age brackets of 11-20, 21-30 and 31-40, reaching 343.0a±28.3 picograms/ml, 316.7abd±41.2 picograms/ml and 295.9b±51.9 picograms/ml respectively, in comparison to the control group. Conversely, the lowest TNF-α level was noted in patients aged 41 (238.0c±42.6 picograms/ml). Moreover, TNF-α concentration was higher in patients with leishmaniasis in rural areas compared to urban areas. In rural regions, the TNF-α concentration was 436.7a±54.4 picograms/ml.

Dynamic Brain Lipid Profiles Modulate Microglial Lipid Droplet Accumulation and Inflammation Under Ischemic Conditions in Mice.

Microglia are critically involved in post-stroke inflammation affecting neurological outcomes. Lipid droplet (LD) accumulation in microglia results in a dysfunctional and pro-inflammatory state in the aged brain and worsens the outcome of neuroinflammatory and neurodegenerative diseases. However, the role of LD-rich microglia (LDRM) under stroke conditions is unknown. Using in vitro and in vivo stroke models, herein accumulation patterns of microglial LD and their corresponding microglial inflammatory signaling cascades are studied. Interactions between temporal and spatial dynamics of lipid profiles and microglial phenotypes in different post-stroke brain regions are found. Hence, microglia display enhanced levels of LD accumulation and elevated perilipin 2 (PLIN2) expression patterns when exposed to hypoxia or stroke. Such LDRM exhibit high levels of TNF-α, IL-6, and IL-1β as well as a pro-inflammatory phenotype and differentially expressed lipid metabolism-related genes. These post-ischemic alterations result in distinct lipid profiles with spatial and temporal dynamics, especially with regard to cholesteryl ester and triacylglycerol levels, further exacerbating post-ischemic inflammation. The present study sheds new light on the dynamic changes of brain lipid profiles and aggregation patterns of LD in microglia exposed to ischemia, demonstrating a mutual mechanism between microglial phenotype and function, which contributes to progression of brain injury.

Antidepressant-like effect of riparin I and riparin II against CUMS-induced neuroinflammation via astrocytes and microglia modulation in mice.

Depression is a common mood disorder and many patients do not respond to conventional pharmacotherapy or experience a variety of adverse effects. This work proposed that riparin I (RIP I) and riparin II (RIP II) present neuroprotective effects through modulation of astrocytes and microglia, resulting in the reversal of depressive-like behaviors. To verify our hypothesis and clarify the pathways underlying the effect of RIP I and RIP II on neuroinflammation, we used the chronic unpredictable mild stress (CUMS) depression model in mice. Male Swiss mice were exposed to stressors for 28 days. From 15 th to the 22 nd day, the animals received RIP I or RIP II (50 mg/kg) or fluoxetine (FLU, 10 mg/kg) or vehicle, by gavage. On the 29 th day, behavioral tests were performed. Expressions of microglia (ionized calcium-binding adaptor molecule-1 - Iba-1) and astrocyte (glial fibrillary acidic protein - GFAP) markers and levels of cytokines tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1β) were measured in the hippocampus. CUMS induced depressive-like behaviors and cognitive impairment, high TNF-α and IL-1β levels, decreased GFAP, and increased Iba-1 expressions. RIP I and RIP II reversed these alterations. These results contribute to the understanding the mechanisms underlying the antidepressant effect of RIP I and RIP II, which may be related to neuroinflammatory suppression.

Using Urine Biomarkers to Differentiate Bladder Dysfunctions in Women with Sensory Bladder Disorders.

Sensory bladder disorders encompass several distinct conditions with overlapping symptoms, which pose diagnostic challenges. This study aimed to evaluate urine biomarkers for differentiating between various sensory bladder disorders, including non-Hunner's interstitial cystitis (NHIC), detrusor overactivity (DO), hypersensitive bladder (HSB), and urodynamically normal women. A retrospective analysis of 191 women who underwent a videourodynamic study (VUDS) was conducted, with some also receiving cystoscopic hydrodistention to confirm the presence of NHIC. Participants were categorized into four groups: DO (n = 51), HSB (n = 29), NHIC (n = 81), and normal controls (n = 30). The urine levels of inflammatory and oxidative stress biomarkers were measured. The DO patients exhibited elevated IP-10 levels, while the HSB patients had decreased TAC and 8-OHdG levels. The NHIC patients showed lower IL-2 and higher TNF-α levels. A TNF-α ≥ 1.05 effectively identified NHIC, with an AUROC of 0.889, a sensitivity of 98.8%, and a specificity of 81.3%. An IP-10 ≥ 6.31 differentiated DO with an AUROC of 0.695, a sensitivity of 56.8%, and a specificity of 72.3%. An 8-OHdG ≤ 14.705 and a TAC ≤ 528.7 identified HSB with AUROCs of 0.754 and 0.844, respectively. The combination of 8-OHdG and TAC provided an AUROC of 0.853 for HSB. These findings suggest that TNF-α, IP-10, TAC, 8-OHdG, and IL-2 are promising non-invasive biomarkers for distinguishing between these conditions, which may improve diagnosis and management.

Serum inflammatory markers as prognostic marker for nasopharyngeal carcinoma with liver metastasis: a multi-center retrospective study.

This retrospective study investigated the prognostic value of serum inflammatory markers in nasopharyngeal carcinoma (NPC) patients, focusing on their association with overall survival (OS) and liver metastasis-free survival (LMFS). The study included 314 NPC patients treated between 2010 and 2020. Clinical characteristics, treatment methods, and serum inflammatory markers were assessed. Patients were categorized into two groups of with and without liver metastasis. Univariate and multivariate Cox regression and Kaplan-Meier survival analyses were performed to investigate the prognostic value of serum inflammatory markers in NPC patients with and without liver metastasis. In the whole cohort, univariate Cox regression analysis singled out tumor necrosis factor-α (TNF-α) (HR = 1.57, 95% CI 1.44-4.90, p = 0.004) and neutrophil-to-lymphocyte ratio (NLR) (HR = 2.13, 95% CI 1.33-3.99, p = 0.009), which were significantly associated with poorer OS. In patients with liver metastasis, TNF-α and NLR could not independently predict OS. However, high TNF-α levels were independently associated with worse OS in patients without liver metastasis (HR (95% CI) = 2.75 (1.67-8.68), p < 0.001). High NLR levels could independently predict poor OS in both groups with (HR (95% CI) = 1.94 (1.77-6.38), p = 0.010) and without liver metastasis (HR (95% CI) = 1.58 (1.19-7.54), p = 0.009). Ultimately, TNF-α and NLR could not significantly predict LMFS. This study highlights the prognostic significance of TNF-α and NLR in NPC patients, especially in those with liver metastasis. These inflammatory markers could serve as valuable indicators for assessing the prognosis of NPC patients. Further research is warranted to validate their clinical utility and explore potential therapeutic implications.

Association between serum cytokines and timeframe for conversion from clinical high-risk to psychosis.

Although many studies have explored the link between inflammatory markers and psychosis, there is a paucity of research investigating the temporal progression in individuals at clinical high-risk (CHR) who eventually develop full psychosis. To address this gap, we investigated the correlation between serum cytokine levels and Timeframe for Conversion to Psychosis (TCP) in individuals with CHR. We enrolled 53 individuals with CHR who completed a 5-year follow-up with a confirmed conversion to psychosis. Granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-1β, 2, 6, 8, 10, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF) levels were measured at baseline and 1-year. Correlation and quantile regression analyses were performed. The median TCP duration was 14 months. A significantly shorter TCP was associated with higher levels of TNF-α (P = 0.022) and VEGF (P = 0.016). A negative correlation was observed between TCP and TNF-α level (P = 0.006) and VEGF level (P = 0.04). Quantile regression indicated negative associations between TCP and GM-CSF levels below the 0.5 quantile, IL-10 levels below the 0.3 quantile, IL-2 levels below the 0.25 quantile, IL-6 levels between the 0.65 and 0.75 quantiles, TNF-α levels below the 0.8 quantile, and VEGF levels below the 0.7 quantile. A mixed linear effects model identified significant time effects for IL-10 and IL-2, and significant group effects for changes in IL-2 and TNF-α. Our findings underscore that a more pronounced baseline inflammatory state is associated with faster progression of psychosis in individuals with CHR. This highlights the importance of considering individual inflammatory profiles during early intervention and of tailoring preventive measures for risk profiles.

Decoding the inflammatory signature of the major depressive episode: insights from peripheral immunophenotyping in active and remitted condition, a case–control study

Depression is a prevalent and incapacitating condition with a significant impact on global morbidity and mortality. Although the immune system’s role in its pathogenesis is increasingly recognized, there is a lack of comprehensive understanding regarding the involvement of innate and adaptive immune cells. To address this gap, we conducted a multicenter case–control study involving 121 participants matched for sex and age. These participants had either an active (or current) major depressive episode (MDE) (39 cases) or a remitted MDE (40 cases), including individuals with major depressive disorder or bipolar disorder. We compared these 79 patients to 42 healthy controls (HC), analyzing their immunological profiles. In blood samples, we determined the complete cell count and the monocyte subtypes and lymphocyte T-cell populations using flow cytometry. Additionally, we measured a panel of cytokines, chemokines, and neurotrophic factors in the plasma. Compared with HC, people endorsing a current MDE showed monocytosis (p = 0.001), increased high-sensitivity C-reactive protein (p = 0.002), and erythrocyte sedimentation rate (p = 0.003), and an altered proportion of specific monocyte subsets. CD4 lymphocytes presented increased median percentages of activation markers CD69+ (p = 0.007) and exhaustion markers PD1+ (p = 0.013) and LAG3+ (p = 0.014), as well as a higher frequency of CD4+CD25+FOXP3+ regulatory T cells (p = 0.003). Additionally, patients showed increased plasma levels of sTREM2 (p = 0.0089). These changes are more likely state markers, indicating the presence of an ongoing inflammatory response during an active MDE. The Random Forest model achieved remarkable classification accuracies of 83.8% for MDE vs. HC and 70% for differentiating active and remitted MDE. Interestingly, the cluster analysis identified three distinct immunological profiles among MDE patients. Cluster 1 has the highest number of leukocytes, mainly given by the increment in lymphocyte count and the lowest proinflammatory cytokine levels. Cluster 3 displayed the most robust inflammatory pattern, with high levels of TNFα, CX3CL1, IL-12p70, IL-17A, IL-23, and IL-33, associated with the highest level of IL-10, as well as β-NGF and the lowest level for BDNF. This profile is also associated with the highest absolute number and percentage of circulating monocytes and the lowest absolute number and percentage of circulating lymphocytes, denoting an active inflammatory process. Cluster 2 has some cardinal signs of more acute inflammation, such as elevated levels of CCL2 and increased levels of proinflammatory cytokines such as IL-1β, IFNγ, and CXCL8. Similarly, the absolute number of monocytes is closer to a HC value, as well as the percentage of lymphocytes, suggesting a possible initiation of the inflammatory process. The study provides new insights into the immune system’s role in MDE, paving the ground for replication prospective studies targeting the development of diagnostic and prognostic tools and new therapeutic targets.

Clinical features, immunologic parameter and treatment outcome of Chinese tuberculosis patients with or without DM.

The coexistence of diabetes mellitus (DM) and pulmonary tuberculosis (PTB) poses a significant health concern globally, with their convergence presenting a considerable challenge to healthcare systems. Previous research has highlighted that comorbidities can mutually influence and exacerbate immune disorders. However, there is a paucity of data on the impact of DM on immunological features and treatment responses in the TB population in China. From January 2020 to June 2022, 264 cases of pulmonary tuberculosis patients (82 DM patients and 182 non-DM patients) hospitalized in our center were selected. 80 patients with TB with DM (TB-DM) and 80 patients with TB without DM (TB-NDM) were enrolled into the final analysis by propensity score matching for age, gender and involved lung field at a ratio of 1:1. The clinical characteristics, immunological features and treatment response were compared between the two groups. After propensity score matching, no differences in the general features such as age gender, involved lung field, the incidence of retreatment and WBC count were found between the two groups. Compared to TB-NDM group, the TB-DM group exhibited a higher positive rate of sputum smear and incidence of cavitary lesions. Immunological features analysis revealed that the TB-DM patients had higher levels of TNF-α [pg/ml; 8.56 (7.08-13.35) vs. 7.64 (6.38-10.14) p = 0.033] and IL-8 [pg/ml; 25.85 (11.63-58.40) vs. 17.56 (6.44-39.08) p = 0.003] but lower CD8+ T lymphocyte count [cells/mm3; 334.02 (249.35-420.71) VS 380.95 (291.73-471.25) p = 0.038]. However, there was no significant difference in serum IL-6 concentration and CD4+ T lymphocyte count between the two groups. After 2 months of anti-tuberculosis treatment, 39 (24.4%) cases had suboptimal treatment response, including 23 (28.7%) TB-DM patients and 16 (20%) TB-NDM patients. There was no difference in suboptimal response rate (SRR) was found between the two groups (p = 0.269). The multivariate logistic regression analysis indicated that retreatment for TB [AOR: 5.68 (95%CI: 2.01-16.08), p = 0.001], sputum smear positivity [AOR: 8.01 (95%CI: 2.62-24.50), p = 0.001] were associated with SRR in all participants, and in TB-DM group, only sputum smear positivity [AOR: 16.47 (1.75-155.12), p = 0.014] was positive with SRR. DM is a risk factor for pulmonary cavity formation and sputum smear positivity in TB population. Additionally, TB-DM patients is characterized by enhanced cytokine responses and decreased CD8+ T lymphocytes. The retreatment for TB and sputum smear positivity were associated with the occurrence of suboptimal treatment response.

Conversion of dendritic cells into tolerogenic or inflammatory cells depends on the activation threshold and kinetics of the mTOR signaling pathway

BackgroundRestoring impaired peripheral immune tolerance is the primary challenge in treating autoimmune diseases. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs), a fraction of low molecular weight proteins, in inhibiting the progression of psoriatic arthritis, even in the presence of high levels of the proinflammatory cytokine TNFα in the bloodstream. When specifically targeting dendritic cells (DCs), SSPs transform them into tolerogenic cells, which efficiently induce the development of regulatory Foxp3+ Treg cells. In this study, we provide further insights into the mechanism of action of SSPs.ResultsWe found that SSPs stimulate the activation of the mTOR signaling pathway in dendritic cells, albeit in a different manner than the classical immunogenic stimulus LPS. While LPS-induced activation is rapid, strong, and sustained, the activity induced by SSPs is delayed, less intense, yet still significant. These distinct patterns of activation, as measured by phosphorylation of key components of the pathway are also observed in response to other immunogenic and tolerogenic stimuli such as GM-CSF + IL-4 or IL-10 and TGFβ. The disparity in mTOR activation between immunogenic and tolerogenic stimuli is quantitative rather than qualitative. In both cases, mTOR activation primarily occurs through the PI3K/Akt signaling axis and involves ERK and GSK3β kinases, with minimal involvement of AMPK or NF-kB pathways. Furthermore, in the case of SSPs, mTOR activation seems to involve adenosine receptors. Additionally, we observed that DCs treated with SSPs exhibit an energy metabolism with high plasticity, which is typical of tolerogenic cells rather than immunogenic cells.ConclusionHence, the decision whether dendritic cells enter an inflammatory or tolerogenic state seems to rely on varying activation thresholds and kinetics of the mTOR signaling pathway.

Engineered dendritic cells-derived exosomes harboring HIV-1 Nefmut-Tat fusion protein and heat shock protein 70: A promising HIV-1 safe vaccine candidate

Antigen presenting cells (APCs)-derived exosomes are nano-vesicles that can induce antigen-specific T cell responses, and possess therapeutic effects in clinical settings. Moreover, dendritic cells (DCs)-based vaccines have been developed to combat human immunodeficiency virus-1 (HIV-1) infection in preclinical and clinical trials. We investigated the immunostimulatory effects (B- and T-cells activities) of DCs- and exosomes-based vaccine constructs harboring HIV-1 Nefmut-Tat fusion protein as an antigen candidate and heat shock protein 70 (Hsp70) as an adjuvant in mice. The modified DCs and engineered exosomes harboring Nefmut-Tat protein or Hsp70 were prepared using lentiviral vectors compared to electroporation, characterized and evaluated by in vitro and in vivo immunological tests. Our data indicated that the engineered exosomes induced high levels of total IgG, IgG2a, IFN-γ, TNF-α and Granzyme B. Moreover, co-injection of exosomes harboring Hsp70 could significantly increase the secretion of antibodies, cytokines and Granzyme B. The highest levels of IFN-γ and TNF-α were observed in exosomes harboring Nefmut-Tat combined with exosomes harboring Hsp70 (Exo-Nefmut-Tat + Exo-Hsp70) regimen after single-cycle replicable (SCR) HIV-1 exposure. Generally, Exo-Nefmut-Tat + Exo-Hsp70 regimen can be considered as a promising safe vaccine candidate due to high T-cells (Th1 and CTL) activity and its maintenance against SCR HIV-1 exposure.

Knockdown of trem2 promotes proinflammatory microglia and inhibits glioma progression via the JAK2/STAT3 and NF-κB pathways

BackgroundIn the tumor immune microenvironment (TIME), triggering receptor expressed on myeloid cells 2 (trem2) is widely considered to be a crucial molecule on tumor-associated macrophages(TAMs). Multiple studies have shown that trem2 may function as an immune checkpoint in various malignant tumors, mediating tumor immune evasion. However, its specific molecular mechanisms, especially in glioma, remain elusive.MethodsLentivirus was transfected to establish cells with stable knockdown of trem2. A Transwell system was used for segregated coculture of glioma cells and microglia. Western blotting, quantitative real-time polymerase chain reaction (qRT‒PCR), and immunofluorescence (IF) were used to measure the expression levels of target proteins. The proliferation, invasion, and migration of cells were detected by colony formation, cell counting kit-8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU) and transwell assays. The cell cycle, apoptosis rate and reactive oxygen species (ROS) level of cells were assessed using flow cytometry assays. The comet assay and tube formation assay were used to detect DNA damage in glioma cells and angiogenesis activity, respectively. Gl261 cell lines and C57BL/6 mice were used to construct the glioma orthotopic transplantation tumor model.ResultsTrem2 was highly overexpressed in glioma TAMs. Knocking down trem2 in microglia suppressed the growth and angiogenesis activity of glioma cells in vivo and in vitro. Mechanistically, knockdown of trem2 in microglia promoted proinflammatory microglia and inhibited anti-inflammatory microglia by activating jak2/stat1 and inhibiting the NF-κB p50 signaling pathway. The proinflammatory microglia produced high concentrations of nitric oxide (NO) and high levels of the proinflammatory cytokines TNF-α, IL-6, and IL-1β, and caused further DNA damage and promoted the apoptosis rate of tumor cells.ConclusionsOur findings revealed that trem2 in microglia plays a significant role in the TIME of gliomas. Knockdown of trem2 in microglia might help to improve the efficiency of inhibiting glioma growth and delaying tumor progression and provide new ideas for further treatment of glioma.

Effect of peripheral blood inflammatory indicators on the efficacy of immunotherapy in patients with advanced non-small cell lung cancer and chronic obstructive pulmonary disease

Objective: To investigate the impact of peripheral blood inflammatory indicators on the efficacy of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) complicated with chronic obstructive pulmonary disease (COPD). Methods: A retrospective cohort study was performed to include 178 patients with Ⅲ-Ⅳ NSCLC complicated with COPD who received at least 2 times of immunotherapy in Xinqiao Hospital of the Army Medical University from January 2019 to August 2021. Baseline peripheral blood inflammatory indicators such as interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α) were collected within 2 weeks before the first treatment, with the last one being on or before February 7, 2022. X-tile software was used to determine the optimal cut-off value of peripheral blood inflammatory indicators. The Cox multivariate regression models were used to analyze the factors affecting progression free survival (PFS) and overall survival (OS). Results: Among the 178 patients, there were 174 males (97.8%) and 4 females (2.2%); the age ranged from 42 to 86 (64.3±8.3) years old.There were 30 cases (16.9%) of immunotherapy monotherapy, 114 cases (64.0%) of immunotherapy combined with chemotherapy, 21 cases (11.8%) of immunotherapy combined with antivascular therapy, and 13 cases (7.3%) of immunotherapy combined with radiotherapy. The median follow-up period was 14.5 months (95%CI: 13.6-15.3 months). The objective response rate (ORR) and disease control rate (DCR) were 44.9% (80/178) and 90.4% (161/178) for the whole group, the median PFS was 14.6 months (95%CI: 11.6-17.6 months), and the median OS was 25.7 months (95%CI: 18.0-33.4 months). The results of Cox multivariate analysis showed that IL-6>9.9 ng/L (HR=5.885, 95%CI: 2.558-13.543, P<0.01), TNF-α>8.8 ng/L (HR=3.213, 95%CI: 1.468-7.032, P=0.003), IL-8>202 ng/L (HR=2.614, 95%CI: 1.054-6.482, P=0.038), systemic immune inflammatory index (SII)>2 003.95 (HR=2.976, 95%CI: 1.647-5.379, P<0.001) were risk factors for PFS, and advanced lung cancer inflammation index (ALI)>171.15 was protective factor for PFS (HR=0.545, 95%CI: 0.344-0.863, P=0.010). IL-6>9.9 ng/L(HR=6.124, 95%CI: 1.950-19.228, P<0.002), lactate dehydrogenase (LDH)>190.7 U/L (HR=2.776, 95%CI: 1.020-7.556, P=0.046), SII>2 003.95 (HR=4.521, 95%CI: 2.241-9.120, P<0.001) were risk factors for OS, and ALI>171.15 was a protective factor for OS (HR=0.434, 95%CI: 0.243-0.778, P=0.005). Conclusion: Baseline high levels of IL-6, TNF-α, IL-8, SII, LDH, and low levels of ALI are risk factors for poor prognosis in patients with advanced NSCLC-COPD receiving immunotherapy.

An Amino Acids and Dipeptide Injection Inhibits the TNF-α/HMGB1 Inflammatory Signaling Pathway to Reduce Pyroptosis and M1 Microglial Polarization in POCD Mice: the Gut to the Brain.

Peripheral surgery-induced neural inflammation is a key pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the mechanism underlying neuroinflammation and associated neural injury remains elusive. Surgery itself can lead to gut damage, and the occurrence of POCD is accompanied by high levels of TNF-α in the serum and blood‒brain barrier (BBB) damage. Reductions in stress, inflammation and protein loss have been emphasized as strategies for enhanced recovery after surgery (ERAS). We designed an amino acids and dipeptide (AAD) formula for injection that could provide intestinal protection during surgery. Through the intraoperative infusion of AAD based on the ERAS concept, we aimed to explore the effect of AAD injection on POCD and its underlying mechanism from the gut to the brain. Here, we observed that AAD injection ameliorated neural injury in POCD, in addition to restoring the function of the intestinal barrier and BBB. We also found that TNF-α levels decreased in the ileum, blood and hippocampus. Intestinal barrier protectors and TNF-α inhibitors also alleviated neural damage. AAD injection treatment decreased HMGB1 production, pyroptosis, and M1 microglial polarization and increased M2 polarization. In vitro, AAD injection protected the impaired gut barrier and decreased TNF-α production, alleviating damage to the BBB by stimulating cytokine transport in the body. HMGB1 and Caspase-1 inhibitors decreased pyroptosis and M1 microglial polarization and increased M2 polarization to protect TNF-α-stimulated microglia in vitro. Collectively, these findings suggest that the gut barrier-TNF-α-BBB-HMGB1-Caspase-1 inflammasome-pyroptosis-M1 microglia pathway is a novel mechanism of POCD related to the gut-brain axis and that intraoperative AAD infusion is a potential treatment for POCD.