Cytokine Profile Research Articles

Mimicking and in vitro validating chronic inflammation in human gingival fibroblasts

ObjectiveThe aim of this study was to identify and validate in vitro conditions that may mimic the translational, cytokine and chemokine profiles observed in human inflamed gingiva in vivo. DesignPrimary human gingiva fibroblast cells (HFIB-G) were cultured under serum starvation conditions (0 – 10 %), supplemented with increasing lipopolysaccharide (LPS) concentrations (0.1, 1, or 10 µg/ml) from two bacterial strains E. coli and P. gingivalis and 0.1, 1, or 10 ng/ml recombinant interleukin 1β (IL-1β), alone or in combinations. The levels of cytokines/chemokines were measured in the cell culture medium by Luminex, and gene expression was quantified by Affymetrix microarrays at 24, 48 and 72 h. ResultsInflammation markers were not elevated after stimulation with P. gingivalis LPS, while E. coli LPS and IL-1β individually increased the secretion of interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) to the cell culture medium. IL-1β administration also increased the secretion of several factors, including tumor necrosis factor (TNFα). However, the combination of 1 µg/ml E. coli LPS, 1 ng/ml IL-1β and serum starvation led to increased secretion of IL-6, TNFα, in addition to other factors found in inflamed tissue. Gene expression analyses revealed that this combination not only enhanced the expression interleukins/chemokines genes but also T helper cell signaling and matrix metalloproteinases. ConclusionSerum reduction in cell culture medium together with the administration of E. coli LPS and IL-1β resulted in gene expression and secreted cytokine/chemokine profiles similar to that found in vivo during chronic inflammation.

Systemic profile of pro-inflammatory and anti-inflammatory cytokines and its changes in patients with cataract after surgery

Background. Due to its high prevalence and morbidity, cataract is an urgent medical and social problem. In recent years, immune inflammation, in particular the immune regulation of dystrophic processes, has been of great importance in the pathogenesis of eye diseases. Immunological disorders play a crucial role in the development of age-related eye diseases (cataract, corneal dystrophy, glaucoma, age-related macular degeneration). The effect of pro-inflammatory and anti-inflammatory cytokines on the development of age-related cataract remains understudied, as well at their role in predicting the course of the postoperative period after extraction of age-related cataract has not been fully stu­died, which determines the relevance of the study. The objective: to assess the state of cytokine profile in patients with age-related cataract by determining the content of pro-inflammatory (IL-1β, IL-6) and anti-inflammatory (IL-4, IL-10) interleukins in blood serum before and after surgical treatment of cataract. Materials and methods. The level of pro-inflammatory (IL-1β, IL-6) and anti-inflammatory cytokines (IL-4, IL-10) was studied before and after surgical treatment in 28 patients with age-related cataract (56 eyes), 8 men and 20 women aged 42 to 82 years. The average age of the patients was 71.79 ± 1.90 years. Serum content of cytokines was determined by the enzyme-linked immunosorbent assay using test systems Vector-Best-Ukraine. Results. There was no excess of IL-1β and IL-6 reference values in the blood serum of patients with age-related cataract prior to surgical treatment. Analysis of the pro-inflammatory IL-6 in these patients depending on sex revealed a significant increase in its level by 1.3 times in men and a significant decrease by 1.1 times in women compared to its average content (p < 0.06 and p < 0.01, respectively). The level of anti-inflammatory IL-4 and IL-10 in the blood serum of the examined patients was within the reference values. When studying the content of pro-inflammatory and anti-inflammatory interleukins in serum depending on sex and age in patients with age-related cataract aged 75 years and older, there was a statistically significant increase in IL-6 and IL-10. In this age group, the level of IL-6 was 1.4 times higher in men compared to women, and IL-10 was 1.8 times higher in women than in men. In patients with age-related cataract after surgical treatment, serum content of pro-inflammatory IL-1β, IL-6 and anti-inflammatory IL-4, IL-10 was higher than levels before surgery. The highest levels of IL-1β, IL-6 were in patients with postoperative corneal edema. Serum content of IL-6 in patients with postoperative corneal edema was higher compared to that of IL-1β. Levels of IL-4, IL-10 were higher in patients with postoperative corneal edema, IL-10 in these patients prevailed over IL-4. Conclusions. In patients with age-rela­ted cataract, the content of pro-inflammatory and anti-inflammatory cytokines in the blood serum corresponds to reference values and has no signi­ficant differences from the control group. However, determination of the cytokine profile in people with age-related cataract revealed a violation of the systemic immunological status depending on age and gender. According to our results, patients with age-related cataract over 75 years of age had a significant increase in the level of pro-inflammatory cytokine IL-6 and anti-inflammatory cytokine IL-10 in blood serum. In this age group, IL-6 was higher in men and IL-10 was higher in women. We also noted the absence of significant differences in the content of IL-1β, which may indicate a more specific value of IL-6 levels for the development of cataract. In patients with age-related cataract after surgical treatment, serum levels of pro-inflammatory IL-1β, IL-6 and anti-inflammatory IL-4, IL-10 were higher than preoperative ones. The highest levels of IL-1β, IL-6 were in the blood serum of patients with postope­rative corneal edema, and a decrease in the level of IL-4, IL-10 was also noted in cases of corneal edema. Serum content of IL-6 in patients with postoperative corneal edema was higher than that of IL-1β, and IL-10 prevailed over IL-4 levels.

Inflammatory cytokine responses in pediatric tuberculosis with or without SARS-CoV-2 seropositivity

To characterize the inflammatory cytokine profiles in children with TB in the presence and absence of SARS-CoV2 seropositivity. This study evaluated cytokine responses in two groups of children with TB: CoV2+ (TB and SARS-CoV2 seropositive) and CoV2- (TB and SARS-CoV2 seronegative). Each group had 30 children, and cytokine levels were measured at baseline, month 3, and 6. At baseline, CoV2+ children exhibited significantly elevated levels of cytokines including IFN-γ, IL-2, TNFα, IL-1α, and IL-6, and reduced levels of IL-1β and IL-18, compared to CoV2- children. No significant differences in cytokine levels between the groups were observed at months 3 and 6. Additionally, a general decline in cytokine levels was noted over the course of treatment in both groups. A positive correlation was found between most cytokines and SARS-CoV2 IgG spike protein levels at baseline and at month 3 in the CoV2+ group. This study is one of the first studies to characterize the systemic inflammatory responses in SARS-CoV2 seropositive and seronegative children with TB from a TB endemic country. The findings enhance our understanding of the immunopathogenesis of TB and SARS-CoV2 seropositivity in children and may inform future therapeutic strategies.

Identification of Severe Acute Exacerbations of Chronic Obstructive Pulmonary Disease Subgroups by Machine Learning Implementation in Electronic Health Records.

Acute exacerbations of COPD (AECOPD) are heterogeneous. Machine learning (ML) has previously been used to dissect some of the heterogeneity in COPD. The widespread adoption of electronic health records (EHRs) has led to the rapid accumulation of large amounts of patient data as part of routine clinical care. However, it is unclear whether the implementation of ML in EHR-derived data has the potential to identify subgroups of AECOPD. Determine whether ML implementation using EHR data from severe AECOPD requiring hospitalization identifies relevant subgroups. This study used two retrospective cohorts of patients with AECOPD (non-COVID-19 and COVID-19) treated at Yale-New Haven Hospital (YNHHS). K-means clustering was used to identify patient subgroups. We identified three subgroups in the non-COVID cohort (n=1,736). Each subgroup had distinct clinical characteristics. The reference subgroup was the largest (n=904), followed by cardio-renal (n = 548) and eosinophilic (n=284). The eosinophilic subgroup had milder severity of AECOPD, including a shorter hospital stay (p<0.01). The cardio-renal subgroup had the highest mortality during (5%) and in the year after hospitalization (30%). Validation of the severe AECOPD classifier in the COVID-19 cohort recapitulated the characteristics seen in the non-COVID cohort. AECOPD subgroups in the COVID-19 cohort had different IL-1 beta, IL-2R, and IL-8 levels (FDR ≤ 0.05. These specific leukocyte and cytokine profiles resulted in inflammatory differences between the AECOPD subgroups based on C-reactive protein levels. Incorporating ML with EHR-data allows the identification of specific clinical and biological subgroups for severe AECOPD.

The Association between Gut Microbiota and Serum Biomarkers in Children with Atopic Dermatitis.

Background. Currently, it is known that the gut microbiota plays an important role in the functioning of the immune system, and a rebalancing of the bacterial community can arouse complex immune reactions and lead to immune-mediated responses in an organism, in particular, the development of atopic dermatitis (AD). Cytokines and chemokines are regulators of the innate and adaptive immune response and represent the most important biomarkers of the immune system. It is known that changes in cytokine profiles are a hallmark of many diseases, including atopy. However, it remains unclear how the bacterial imbalance disrupts the function of the immune response in AD. Objectives. We attempted to determine the role of gut bacteria in modulating cytokine pathways and their role in atopic inflammation. Methods. We sequenced the 16S rRNA gene from 50 stool samples of children aged 3-12 years who had confirmed atopic dermatitis, and 50 samples from healthy children to serve as a control group. To evaluate the immune status, we conducted a multiplex immunofluorescence assay and measured the levels of 41 cytokines and chemokines in the serum of all participants. Results. To find out whether changes in the composition of the gut microbiota were significantly associated with changes in the level of inflammatory cytokines, a correlation was calculated between each pair of bacterial family and cytokine. In the AD group, 191 correlations were significant (Spearman's correlation coefficient, p ≤ 0.05), 85 of which were positive and 106 which were negative. Conclusions. It has been demonstrated that intestinal dysbiosis is associated with alterations in cytokine profiles, specifically an increase in proinflammatory cytokine concentrations. This may indicate a systemic impact of these conditions, leading to an imbalance in the immune system's response to the Th2 type. As a result, atopic conditions may develop. Additionally, a correlation between known AD biomarkers (IL-5, IL-8, IL-13, CCL22, IFN-γ, TNF-α) and alterations in the abundance of bacterial families (Pasteurellaceae, Barnesiellaceae, Eubacteriaceae) was observed.

Changes in vaginal cytokines concentrations during artificial insemination and natural service in beef heifers

ObjectiveHeifer development is crucial for the optimization of reproductive efficiency in beef production. Heifer development is largely influenced by nutrition. Nutritional status of these heifers can influence immunological responses that are crucial for reproduction. Commercial Angus heifers (n = 9) were utilized, in a pilot study, to elucidate the effects of sampling time (days 0, 7, 14, 21, 28, and 35), pregnancy status, and type of mating on individual cytokine concentrations and cytokine profiles in the vagina following breeding.ResultsCytokine profiles were analyzed using MetaboAnalyst 5.0 and one-way ANOVAs were performed in R Studio to identify differences in individual cytokines based on sampling time, pregnancy status, and type of mating. Cytokine profiles were different (P = 0.05) 7 days after either mating type. Cytokines, IL-1β, IL-17a, MCP-1, and TNFα were different based on the mating type and pregnancy status. Multiple cytokines, IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-17a, VEGFa, and MIP1α, were different between days regardless of pregnancy status. In conclusion, vaginal cytokines differ based on pregnancy status, type of mating, and time which may be indicative of vital pathways that need to be activated for pregnancy.

Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade

The efficacy and side effects of radiotherapy (RT) depend on parameters like dose and the volume of irradiated tissue. RT induces modulations of the tumor immune microenvironment (TIME) that are dependent on the dose. Low dose RT (LDRT, i.e., single doses of 0.5–2 Gy) has been shown to promote immune infiltration into the tumor. Here we hypothesize that partial tumor irradiation combining the immunostimulatory/non-lethal properties of LDRT with cell killing/shrinkage properties of high dose RT (HDRT) within the same tumor mass could enhance anti-tumor responses when combined with immunomodulators. In models of colorectal and breast cancer in immunocompetent female mice, partial irradiation (PI) with millimetric precision to deliver LDRT (2 Gy) and HDRT (16 Gy) within the same tumor induces substantial tumor control when combined with anti-PD1. Using flow cytometry, cytokine profiling and single-cell RNA sequencing, we identify a crosstalk between the TIME of the differentially irradiated tumor volumes. PI reshapes tumor-infiltrating CD8+ T cells into more cytotoxic and interferon-activated phenotypes but also increases the infiltration of pro-tumor neutrophils driven by CXCR2. The combination of the CXCR2 antagonist SB225002 with PD1 blockade and PI improves tumor control and mouse survival. Our results suggest a strategy to reduce RT toxicity and improve the therapeutic index of RT and immune checkpoint combinations.

The cytokine profile correlates with less tumor-infiltrating lymphocytes in luminal A breast cancer.

Tumor-infiltrating lymphocyte (TIL) levels are prognostic and predictive factors for breast cancer. Unlike other subtypes, most luminal A breast cancers are immune deserts; however, the underlying mechanisms are poorly understood. Immune-related cytokines, chemokines, and growth factors were measured in the sera of 103 patients with breast cancer using a multiplex panel. The TILs were evaluated for hotspot lesions. Circulating interleukin 1 receptor antagonist (IL-1ra), IL-8, IL-12, IL-17, macrophage inflammatory protein-1β (MIP-1b), and platelet-derived growth factor B homodimer (PDGF-bb) concentrations were significantly associated with TIL levels. Cluster analysis using these six variables identified six clusters related to TIL levels. Breast cancers with high TILs (≥ 50%) were most frequent in cluster 3 (9 out of 15 cases, 60.0%), followed by cluster 1 (8 out of 34 cases, 23.5%), and the fewest in cluster 6 (1 out of 21 cases, 4.8%), whereas only one or three cases were present in clusters 2, 4, and 5 (p = 0.0064). Cluster 6, consisting mostly of luminal A (19 out of 21 cases, 90.5%), showed high levels of IL-12, IL-17, and PDGF-bb, and low levels of MIP-1b. We identified a luminal A-associated immunosuppressive cytokine signature in circulation. These results suggest that a tumor microenvironment with high levels of IL-17 and PDGF-bb, and low levels of MIP-1b in luminal A breast cancers results in low induction of TILs. Our data may partially explain the low TIL levels observed in the patients with luminal A breast cancer.

Cytokines profile in occult hepatitis B virus infections in blood donors at the National Blood Transfusion Center of Lomé, Togo

Aims: Occult hepatitis B infection (OBI) was detected in blood donors at the National Blood Transfusion Center (CNTS) of Lomé. This constitutes a risk of transmission of the OBI to transfused patients since the detection of this infection is not systematic. The aim of this study is to describe the profile of cytokines in blood donors with OBI at CNTS of Lomé in Togo. Methods: This is a prospective study during which the cytokines IL-6, TNFα, IL-5, IL-10, IL-17A, and IFNγ were measured by using a sandwich enzyme-linked immunosorbent assay (ELISA) at two time points: initially (D0) in August 2022 and again seven months later (+7 months) in April 2023, in blood donors with occult hepatitis B infection. Results: At D0, the cytokine profile in sera of occult hepatitis B donors showed a significant reduced level of IL-6 (p=0.0009), TNFα (p=0.0025), IL-5 (p=0.0011), and IL-17A (p=0.0218) compared to non-occult hepatitis B donors. The inflammatory cytokine IFNγ and the regulatory cytokine IL-10 were also reduced but the differences were not significant. After seven months, the sera cytokine profile of occult hepatitis B donors had not changed, showing a significant reduced level of IL-6 (p=0.0005), TNFα (pgreater 0.0001), IL-5 (p=0.0234), and IL-17A (p greater 0.0001). We noticed especially for IL-17A, undetectable levels. Conclusion: Several authors have highlighted the presence of inflammatory cytokines in their studies; however, in our study, we noticed a downregulation or an absence of inflammatory cytokines in donors with occult hepatitis B.

Intravenous administration of muse cells improves cerebral ischemia outcome via immunomodulation in the spleen.

Ischemic stroke is a leading cause of disability and death globally. Stem cell therapies are emerging as a frontier for enhancing post-stroke recovery, with Muse cells-a subclass of pluripotent stem cells-demonstrating considerable promise. Muse cells are notable not only for their potential in cell replacement but also for their role in modulating immune responses following cerebral infarction. In the present study, we administered Muse cells intravenously to mice after inducing a stroke via distal middle cerebral artery occlusion. We evaluated motor outcomes, splenocyte populations, cytokine profiles, and gene expression 2 weeks after inducing stroke. Additionally, comparisons were drawn between outcomes in splenectomized mice and those receiving adoptive splenocyte transfer to discern the specific influence of the spleen on treatment efficacy. Our findings revealed that Muse cell therapy facilitates motor recovery, an effect that is compromised in the absence of the spleen. Spleens in treated mice exhibited a shift in neutrophil counts, increased cytokine activity, and a notable uptick in the expression of genes related to protein folding. These insights affirm the potential therapeutic effect of Muse cells in post-stroke treatment strategies, with their efficacy attributed, at least in part, to immunomodulatory pathways involving the spleen.

Severe myelotoxicities related to Th1, Th2, Th17 and Treg CD4+ T cells subpopulations and their cytokine profiles in Mexican children with acute lymphoblastic leukemia during induction of chemotherapy

Abstract Background Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer in the world, and the myelotoxicities due to chemotherapy can lead to severe infections and hemorrhages with high morbidity and mortality. The immune response has implications in the severity of cancer or survival. This immune response is associated with the predominant subpopulations CD4+ T cells and their effector cytokines. However, it is not known if the immune responses are associated with severe myelotoxicities and mortality in children with ALL. Methods To evaluate the contributions of immunological factors on ALL severe myelotoxicities, we identified the Th1, Th2, Th9, Th17, Th22 and Tregs subpopulations of CD4+ T cells according to their chemokine receptor expression patterns in peripheral blood mononuclear cells by flow cytometry. We evaluated also their cytokines levels by Milliplex in serum from 10 children with ALL at diagnosis (day 0), during induction (day 19) and at the end of induction (day 30) between April 2022 and July 2023. Clinical characteristics such age, sex, type and risk of ALL, hemoglobin and platelets levels, absolute neutrophil count, grade of severity and type of myelotoxicities, infections, and hemorrhages were collected. Clinical outcomes as hospitalization care requirements, ICU admission, leukemia remission or relapsed and mortality were followed and documented. Results The age of children was 8.9 years, (SD,5.6; range 2-16), 60% were male sex, all children had pre- B ALL diagnosis, and 80% were intermediate risk-ALL. Th1 cells were predominant at diagnosis (8.1%) and at the end of induction (7.8%), and Th2 cells at day 19 (7.4%), whereas Th17 were significantly decreased at day 30 (2.6%) (p&amp;lt;0.05). Four patients presented bloodstream infection, two by Gram-positive bacteria (Micrococcus, and Streptococcus), one by Klebsiella pneumoniae antimicrobial resistant, and one by Trichosporum asahii. Severe myelotoxicities were presented in 20% of the patients at day19, and in 30% at day 30. Remission was documented in all patients at day 30 and one was identified with early relapse in the follow-up. Three patients (30%) presented poor outcomes, requiring care in ICU and one died (10%) due to fungal infection. Treg cells were significantly predominant in the children who died by fungal infection (p&amp;lt;0.05), with IL-10 level of 84.6 pg/mL but not detectable IL-35 levels. Conclusion Th17 and Treg subpopulations of CD4+ T cells can play an essential role in immune microenvironment during induction related with the severity of the myelotoxicities and infections, and cytokine IL-10 could be used as marker of infection outcome.

The Protective Role of Transcription Factor Nrf2 in Murine Macrophage Activation Syndrome.

Macrophage activation syndrome (MAS) is characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. Transcription factor Nrf2 is a master regulator of redox homeostasis. In this work we aim to investigate the role of Nrf2 in murine hyperinflammation and the mechanisms by which Nrf2 activation by red blood cell products regulates pro-inflammatory cytokine production. We induce murine MAS in wildtype and Nrf2 knockout (Nrf2 -/-) mice by repeat administration of TLR9-agonist CpG. Clinical and biochemical markers of disease were measured including complete blood counts, liver and spleen pathology, serum free heme, ferritin, and cytokine profiles. In vitro bone marrow derived macrophages and dendritic cells were used to investigate regulation of CpG-induced cytokine expression by oxidized red blood cells and hemin. Patients with hyperinflammatory disease have higher levels of Nrf2 gene expression. Mice with CpG-induced hyperinflammation have elevated systemic lipid peroxidation which is exacerbated in Nrf2 -/- mice. Compared to wildtype controls, Nrf2 -/- mice develop significantly worse organomegaly, organ pathology, and reticulocytosis. Nrf2 -/- mice have exacerbated hypercytokinemia in cytokines central MAS physiology: IL-12, IFNg, and IL-10. In vitro we found that oxidized red blood cell lysates and hemin are able to suppress IL-12 transcription and protein production from bone marrow derived dendritic cells in a Nrf2-dependent manner. Together our findings show that transcription factor Nrf2 is highly expressed in patients with hyperinflammatory disease and demonstrate a protective role for Nrf2 in a murine model of MAS in part due to Nrf2-mediated suppression of proinflammatory cytokine production.

Mechanisms of drug resistance to neoadjuvant chemotherapy in breast cancer

Aim. Тo study the molecular genetic characteristics of the tumor microenvironment and the mechanisms of cell death in resistant locally advanced breast cancer.Materials and methods. The study included 48 patients with breast cancer T2–4N0–3M0–1 (mean age 55.6 ± 9.8 years), and 29 patients of comparable age with breast fibroadenoma. According to the design of the study, patients were divided into groups: Group 1 included women with breast cancer resistant to neoadjuvant chemotherapy (n = 23), Group 2 – with breast cancer and a complete response to neoadjuvant chemotherapy (n = 25), control Group – with fibroadenoma (n = 29). The expression of markers CD4+, CD8+, CD20+, CD68+, tumor necrosis factor α (TNF-α), vascular endothelial growth factor A (VEGF A), Ang-2, matrix metalloproteinase 12 (MMP-12), inducible nitric oxide synthase (iNOS), bcl-2, p53, CD95 was assessed using immunohistochemistry.Results. When phenotyping immune cells, the following differences were obtained: in the tumor tissue of patients in Group 1, a significant decrease in the number of cytotoxic CD8+ cells was noted compared to Group 2 (p = 0.001) and control (p = 0.032). In Group 2, a significant increase in the number of CD68+ cells was revealed in relation to Group 1 (p = 0.027). The cytokine profile of the tumor microenvironment in Group 1 is characterized by statistically significant overexpression of TNF-α compared to Group 2 (p &gt;0.001) and the control Group (p = 0.01). With regard to apoptotic factors, noteworthy is the significant decrease in the expression of bcl-2 and p53 in Group 1 compared to Group 2 (p = 0.001 and p = 0.02 accordingly).Conclusion. The presented results can serve as the basis for the creation of diagnostic algorithms that have predictive value regarding the effectiveness of NCT, and also to help identify new targets to justify the use of combined breast cancer treatments in the early stage.

Expression profile of Toll-like receptors and cytokines in the cecal tonsil of chickens challenged with Eimeria tenella.

Chicken coccidiosis, caused by Eimeria spp., seriously affects the development of the poultry breeding industry. Currently, extensive studies of chicken coccidiosis are mostly focused on acquired immune responses, while information about the innate immune response of chicken coccidiosis is lacking. Toll-like receptor (TLR), the key molecule of the innate immune response, connects innate and adaptive immune responses and induces an immune response against various pathogen infections. Therefore, the quantitative real-time PCR was used to characterize the expression profile of chicken TLRs (chTLRs) and associated cytokines in the cecal tonsil of chickens infected with Eimeria tenella. The results showed that the expression of chTLR1a, chTLR2a, and chTLR5 was significantly upregulated at 3h post-infection, while chTLR1b, chTLR2b, chTLR3, chTLR7, chTLR15 and chTLR21 was significantly downregulated (p < 0.05). In addition, chTLR1a expression rapidly reached the peaked expression at 3h post-infection, while chTLR2b and chTLR15 peaked at 168h post-infection, and chTLR2a expression was highest among chTLRs, peaking at 48h post-infection (p < 0.05). For cytokines, interleukin (IL)-6 and tumor necrosis factor (TNF)-α peaked at 96h post-infection, IL-4 and IL-12 peaked at 144h post-infection, and interferon-γ expression was highest among cytokines at 120h post-infection. In addition, IL-12 and IL-17 were markedly upregulated at 6h post-infection (p < 0.05). These results provide insight into innate immune molecules during E. tenella infection in chickens and suggest that innate immune responses may mediate resistance to chicken coccidiosis.

Major depressive disorder, neuroticism, suicidal behaviors, and depression severity are associated with cytokine networks and their intricate interactions with metabolic syndrome

ObjectivesTo identify alterations in the immune profiles in outpatients with major depression (MDD), and its associations with key features, such as suicidal ideation, neuroticism, cognitive symptoms, and the depression phenome while accounting for metabolic syndrome (MetS). MethodsIn this case-control study, we assayed 48 serum cytokines, chemokines, and growth factors in 67 healthy controls and 66 MDD outpatients. Around 50 % of the outpatient MDD and control participants had a diagnosis of MetS. ResultsTen differentially expressed proteins (DEPs) were upregulated in outpatient MDD (i.e., CXCL12, tumor necrosis factor [TNF]β, platelet-derived growth factor [PDGF], CCL11, interleukins [IL]9, IL4, CCL5, CCL2, CCL4, IL1 receptor antagonist [IL1RN]), indicating an immune and defense response. Six DEPs were downregulated (vascular endothelial growth factor A [VEGFA], IL12, CCL3, colony stimulating factor [CSF]1, IL1B, nerve growth factor [NGF]), indicating lowered neurogenesis and neuron death regulation. Significant interactions between outpatient MDD and MetS caused a) substantial increases in IL4, IL17, TNF, TNFB, CCL2, CCL5, PDGF, IL1RN; and b) downregulation of VEGFA and FGF. A large part of the variance in neuroticism (26 %), suicidal behaviors (23 %), and the MDD phenome (31 %) was predicted by immunological data and interactions between MetS and CCL5, TNFB or VEGFA. ConclusionOutpatient MDD is characterized by a cytokine profile with neurotoxic potential which partly explains neuroticism, suicidal behaviors, and the phenome's severity. Lowered IL-10 and activated cytokine profiles with neurotoxic potential are characteristics of outpatient MDD and other depression phenotypes, including severe first-episode inpatient MDD. The presence of MetS in outpatient MDD considerably activates immune profiles with neurotoxic potential. Consequently, immune studies in MDD should always be performed in subjects with and without MetS.

Macro- and Microstructural White Matter Differences in Neurologic Postacute Sequelae of SARS-CoV-2 Infection.

Neuropsychiatric complications of SARS-CoV-2 infection, also known as neurologic postacute sequelae of SARS-CoV-2 infection (NeuroPASC), affect 10%-60% of infected individuals. There is growing evidence that NeuroPASC is a multi system immune dysregulation disease affecting the brain. The behavioral manifestations of NeuroPASC, such as impaired processing speed, executive function, memory retrieval, and sustained attention, suggest widespread WM involvement. Although previous work has documented WM damage following acute SARS-CoV-2 infection, its involvement in NeuroPASC is less clear. We hypothesized that macrostructural and microstructural WM differences in NeuroPASC participants would accompany cognitive and immune system differences. In a cross-sectional study, we screened a total of 159 potential participants and enrolled 72 participants, with 41 asymptomatic controls (NoCOVID) and 31 NeuroPASC participants matched for age, sex, and education. Exclusion criteria included neurologic disorders unrelated to SARS-CoV-2 infection. Assessments included clinical symptom questionnaires, psychometric tests, brain MRI measures, and peripheral cytokine levels. Statistical modeling included separate multivariable regression analyses of GM/WM/CSF volume, WM microstructure, cognitive, and cytokine concentration between-group differences. NeuroPASC participants had larger cerebral WM volume than NoCOVID controls (β = 0.229; 95% CI: 0.017-0.441; t = 2.16; P = .035). The most pronounced effects were in the prefrontal and anterior temporal WM. NeuroPASC participants also exhibited higher WM mean kurtosis, consistent with ongoing neuroinflammation. NeuroPASC participants had more self-reported symptoms, including headache, and lower performance on measures of attention, concentration, verbal learning, and processing speed. A multivariate profile analysis of the cytokine panel showed different group cytokine profiles (Wald-type-statistic = 44.6, P = .046), with interferon (IFN)-λ1 and IFN-λ2/3 levels higher in the NeuroPASC group. NeuroPASC participants reported symptoms of lower concentration, higher fatigue, and impaired cognition compatible with WM syndrome. Psychometric testing confirmed these findings. NeuroPASC participants exhibited larger cerebral WM volume and higher WM mean kurtosis than NoCOVID controls. These findings suggest that immune dysregulation could influence WM properties to produce WM volume increases and consequent cognitive effects and headaches. Further work will be needed to establish mechanistic links among these variables.

Differential expression and significance of cytokines in cerebrospinal fluid of patients with viral encephalitis

To extensively identify cerebrospinal fluid (CSF) cytokine profiles related to the occurrence, development and prognosis of viral encephalitis (VE) patients by using a high-throughput proteomic approach.We measured 80 cytokines in the CSF of acute-phase VE patients (n = 11) using high-throughput protein chip technology, comparing them to controls (n = 6). ELISA validated these findings and assessed additional cytokines from prior literature in a larger cohort (15 VE patients, 15 controls). Correlations between biomarkers and clinical characteristics were also examined.In the initial stage, we identified two differentially expressed cytokines: cathepsin-L (CTSL), which was up-regulated, and Fractalkine, which was down-regulated. Functional enrichment analysis revealed that these proteins are linked to inflammation, apoptosis, autophagy, and blood-brain barrier disruption. In stage2, the elevations of cathepsin-L (CTSL), fractalkine, interleukin-6 (IL-6), IL-1β, macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α), insulin-like growth factor Ⅱ (IGF-2) and CXC chemokine ligand 10 (CXCL10) in VE were validated by ELISA. The results of linear regression indicated that these cytokines was positively correlated with CSF reactive lesions (p < 0.05).In this study, some biomarkers related with CSF level changes and prognosis were obtained. Although these cytokines are not specific, they may be related to the occurrence and development of VE. CTSL, MIF, IL-1β, TNF-α and CXCL10 can be used as VE potential biomarkers. These cytokines may participate in the pathogenesis of VE through inflammatory response, cell apoptosis, autophagy, blood-brain barrier disruption and cytokine-cytokine receptor interaction pathway.

Cytokine profiles and their correlation with clinical and blood parameters in rheumatoid arthritis and systemic lupus erythematosus.

The abnormal biological activity of cytokines and their imbalance are implicated in developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cytokine levels were measured in RA and SLE patients and compared to healthy controls using the Wilcoxon rank sum test and Kruskal-Wallis test. The relationship between cytokine levels and blood and clinical parameters was assessed using Spearman's correlation test. Compared to healthy controls, both RA and SLE patients exhibited elevated levels of GM-CSF, CX3CL1, IFN-α2, IL-12p70, IL-17A, TNF-α, IL-1β, and IFN-γ, which is evidence of their shared inflammatory signature. IL-2 levels were elevated exclusively in RA patients, while MCP-1 and IL-10 were uniquely increased in SLE patients. Notably, TNF-α showed the most significant increase in SLE patients. IL-4 was elevated in SLE patients with nephritis, correlating with IL-6, IL-10, sCD40L, and IL-8, suggesting B cell involvement in lupus nephritis. The negative correlation between CX3CL1 and TNF-α with HDL in RA and SLE respectively, highlights the potential association of these inflammatory markers with cardiovascular risk. These findings underscore the complex cytokine interplay in RA and SLE. CX3CL1 emerges as a potential therapeutic target for RA, while TNF-α and IL-4 show promise as therapeutic targets for SLE.

The Effects of Marine Fungal Asterripeptides A-C on In Vitro and In Vivo Staphylococcus aureus Skin Infection.

Objectives: This study aimed to investigate the in vitro and in vivo antibacterial and cytoprotective activities of marine fungal tripeptide derivatives with cinnamic acid moiety asterripeptides A-C (1-3). Methods: The antimicrobial and antibiofilm activities of asterripeptides A-C were tested using the Staphylococcus aureus ATCC 21027 strain. Human HaCaT keratinocytes infected with S. aureus were used for the in vitro investigation of the various aspects of the influence of asterripeptides A-C by lumino- and fluorospectrometry, ELISA, flow cytometry, Western blotting, and microscopy techniques. In the in vivo experiments, mice with burns and scalped S. aureus-infected wounds were used according to ethical committee resolution. Results: Asterripeptides A-C (10 µM) inhibited S. aureus growth and biofilm formation. Asterripeptides A-C increased the viability, proliferation, and migration of S. aureus-infected HaCaT cells and reduced the release of reactive oxygen species (ROS), NO, TNF-α, and IL-18. Asterripeptides A-C protected HaCaT cells against TNF-α-induced inflammation, decreased the transcriptional level of NF-κB in JB6 Cl41 cells, and increased the protein levels of Nrf2 and glutathione synthetase in HaCaT cells. More active asterripeptide C was tested in in vivo burn wounds and S. aureus-infected incised wounds. Asterripeptide C significantly enhanced wound healing, normalized cytokine levels and profiles of peripheral blood samples, and decreased S. aureus contamination of wounds and blood in mice with infected incised wounds. Conclusions: Taken together, these results confirm the dual antibacterial and Nrf2-dependent anti-inflammatory activities of asterripeptides A-C in in vitro and in vivo assays.

Increased CD14+HLA-DR-/low myeloid-derived suppressor cells can be regarded as a biomarker on disease severity and response to therapy in acute coronary syndrome.

This study aimed to investigate the dynamic changes in monocytic myeloid-derived suppressor cells (M-MDSCs) and their implications in the pathogenesis of acute coronary syndrome (ACS), shedding light on potential therapeutic targets. Peripheral blood samples were collected from 68 ACS patients, 35 stable angina pectoris (SAP) patients, and 30 healthy controls (HC). Multi-parameter flow cytometry was employed for analysis of M-MDSCs, explored with disease characteristics and progression. ACS patients exhibited an increased frequency of circulating M-MDSCs compared to SAP patients and HC. M-MDSCs levels demonstrated associations with ACS type, coronary artery lesions, multi-vessel disease, and cardiac dysfunction severity. Higher M-MDSCs levels were found in obese patients. Notably, therapy led to a significant decrease in M-MDSCs frequency. Furthermore, ACS patients exhibited elevated levels of interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-α (TNF-α) in the cytokine profile associated with M-MDSCs. Increased expression of arginase-1(Arg-1) was observed in ACS patients, with positive correlations between M-MDSCs levels and IL-6, GM-CSF, and Arg-1 expression. The diagnostic performance of triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and M-MDSCs levels varied in predicting the severity of coronary artery stenosis, with TG showing higher specificity, HDL-C displaying higher sensitivity, and M-MDSCs levels demonstrating balanced sensitivity and specificity. Assessment of M-MDSCs frequency holds promise as a predictive marker for disease progression and therapy response of coronary artery stenosis. The elevated presence of M-MDSCs suggests their potential role in modulating ACS-related inflammation.