Elevated Levels Of IL-6 Research Articles

Biomarkers of type 2 and non-type 2 inflammation in asthma exacerbations.

In adult-onset asthma, two major endotypes have been proposed: T2 with eosinophilia and non-T2 characterised by neutrophils and interleukin (IL)-17. The objective of the study was to examine the endotype marker profile in patients with severe asthma who were hospitalized for exacerbations, with a focus on differentiating between viral and non-viral triggers. Forty-nine patients with asthma, admitted for exacerbations, and 51 healthy controls (HCs) were recruited. We further categorized the exacerbated asthma patients into two groups: non-viral infected (n = 38) and viral infected (n = 11) groups. Blood was drawn and a nasopharyngeal swab taken at the time of admission and eosinophil numbers, eosinophil cationic protein (ECP), immuno- globulin E (IgE), tryptase and viral infection were determined. Additionally, levels of IL-17, IL-33 and IL-31 were assessed. The majority of patients had adult onset asthma (age of diagnosis, 42.8 ±16.1) with a duration of 7.7 ±10.8 years, 24.5% being atopic. Patients had higher levels of eosinophils, ECP and IgE than healthy controls (eosinophils, p = 0.003; ECP and IgE, p = 0.0001). Immunohistochemistry confirmed eosinophils as a source of ECP. Tryptase (p = 0.0001), IL-17 (p = 0.0005), IL-31 (p = 0.0001) and IL-33 (p = 0.0002) were also higher in patients than controls. ECP correlated with tryptase (r = 0.08, p = 0.62). IL-17 showed the best correlation with other mediators, including ECP (r = 0.35, p = 0.24), tryptase (r = 0.69, p = 0.0001), IgE (r = 0.50, p = 0.0001), IL-33 (r = 0.95, p = 0.0001) and IL-31 (r = 0.89, p = 0.0001). IgE, IL-17, and IL-31 had a high AUC when differentiating those with severe and non-severe asthma. The group with exacerbated viral infection showed elevated levels of serum IL-17 and IL-31 compared to the non-infected group. Patients with asthmatic exacerbations were found to have higher levels of both T2 and non-T2 inflammatory markers than healthy controls. In the study, levels of IgE, IL-17, and IL-31 differentiated between patients with severe and non-severe asthma. The last two cytokines were also able to distinguish between exacerbated asthma caused by viral infection and exacerbated asthma caused by non-viral infection.

The impact of AIM2 inflammasome-induced pyroptosis on acute gouty arthritis and asymptomatic hyperuricemia patients.

This study aimed to evaluate the role of absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the pathogenesis of acute gouty arthritis (AGA) and asymptomatic hyperuricemia(AHU). A cohort of 30 AGA patients, 30 AHU individuals, and 30 healthy controls (HC) was assembled. Demographic and biochemical data, along with blood samples, were collected. Serum double-stranded DNA (dsDNA) levels were quantified using a fluorescent assay. Transcriptomic and proteomic analysis of AIM2, Caspase-1, GSDMD, IL-1β, and IL-18 in peripheral blood mononuclear cells was performed using qRT-PCR and Western blot. Enzyme-linked immunosorbent assay (ELISA) was employed to measure serum IL-1β and IL-18. Spearman correlation analysis was utilized to assess relationships between variables. Both AGA and AHU groups demonstrated elevated metabolic indicators and serum levels of dsDNA, IL-1β, and IL-18 compared to the HC group. AGA patients exhibited higher inflammatory markers than the AHU group. In the AGA group, there was a significant increase in the mRNA and protein levels of AIM2, Caspase-1, GSDMD, IL-1β, and IL-18 (P<0.05 to P<0.001). The AHU group showed higher AIM2, Caspase-1, GSDMD, and IL-18 mRNA levels than the HC group (P<0.001 to P<0.01), with a non-significant increase in AIM2, GSDMD, and IL-1β proteins (P>0.05). In contrast, Caspase-1 and IL-18 proteins were significantly higher in the AHU group (P<0.05). Notable correlations were observed between AIM2 protein expression and levels of Caspase-1 and GSDMD in both AGA and AHU groups. In the AGA group, AIM2 protein correlated with IL-1β, but not in the AHU group. The AIM2 protein in the AHU group was positively associated with IL-18, with no such correlation in the AGA group. AIM2 inflammasome may play a role in the inflammatory processes of AGA and AHU and that its activation may be related to the pyroptosis pathway.

Dose-Dependent Prophylactic Efficacy of Filarial Antigens Glutathione-S-Transferase and Abundant Larval Transcript-2 against Brugia malayi Challenge in Mastomys.

To identify the most effective dose of filarial rBmALT-2 and rWbGST alone or in combination against B. malayi infection in vitro and in vivo. Mastomys (n = 5-7/group) received intramuscular (i.m.) injection with three different doses (25, 50, and 100 μg) of rBmALT-2 or rWbGST, either alone or in combination with alum as the adjuvant. Protective immunity was studied by in vivo and in vitro cytotoxicity assay. To evaluate the cellular immune response, splenocyte proliferation and cytokine profile were assessed. Serological results revealed a substantial (p < 0.005) induction of IgG1, IgG2a, and IgG3 responses in vaccinated Mastomys. Mastomys immunized with 50 μg rBmALT-2 + alum induced 79-81% killing against the L3 larvae challenge in vivo and in vitro ADCC assay (p < 0.005); whereas rWbGST + alum alone or in combination with rBmALT-2 + alum induced 63-68% killing (p < 0.005) in vivo and in vitro. Antigen-specific cytokine profiles of Mastomys vaccinated with either BmALT-2, WbGST or a combination showed elevated IL-10, IL-4, and IFN-γ levels, signifying both Th1 and Th2 immune response. These findings suggest that immunization of Mastomys with a 50 μg/dose of rBmALT-2 + alum four times at a 4-week interval demonstrated considerable protection against B. malayi infection.

The Pharmacological Mechanisms Underlying the Protective Effect of Ginsenoside Rg3 against Heart Failure.

Heart failure represents the terminal stage of various cardiovascular diseases. This study aims to explore the pharmacological mechanisms underlying the protective effect of Ginsenoside Rg3 against heart failure. Potential targets of Ginsenoside Rg3 were identified using SwissTargetPrediction and the Comparative Toxicogenomics Database, while heart failure-related genes were retrieved from the Comparative Toxicogenomics Database, Therapeutic Target Database, DisGeNET, and PharmGKB. Overlapping of Ginsenoside Rg3 targets with heart failure-related genes identified drug-disease interaction genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on the drug-disease interaction genes to elucidate their biological functions. A protein-protein interaction network was constructed using the drug-disease interaction genes, and the hub genes were identified by topological analysis. Additionally, we validate the expression of IL-6 and TNF by real-time PCR. The intersection of Ginsenoside Rg3 targets and heart failure-related genes yielded 15 drug-disease interaction genes. Enrichment analysis highlighted the involvement of inflammation-related GO terms and KEGG pathways, such as positive regulation of interleukin-8 and -6 production, regulation of immune effector process, cytokine receptor binding, cytokine activity, adipocytokine signaling pathway, and IL-17 signaling pathway, which are implicated in the cardioprotective effect. Topological analysis revealed four hub genes: STAT3, CASP3, TNF, and IL-6. The application of Ginsenoside Rg3 significantly reversed the elevated levels of IL-6 and TNF in the isoproterenol-treated H9c2 cell line. Our findings suggest that the cardioprotective effect of Ginsenoside Rg3 may be mediated through its anti-inflammation properties. Further research is required to elucidate and validate the detailed cardioprotective mechanisms of Ginsenoside Rg3.

An adjuvant formulation containing Toll-like Receptor 7 agonist stimulates protection against morbidity and mortality due to Anaplasma marginale in a highly endemic region of west Africa.

Efficient cattle production and provision of animal-sourced foods in much of Africa is constrained by vector-borne bacterial and protozoal diseases. Effective vaccines are not currently available for most of these infections resulting in a continuous disease burden that limits genetic improvement. We tested whether stimulation of innate immunity using the Toll-like Receptor (TLR) 7 agonist imiquimod, formulated with saponin and water-in-oil emulsion, would protect against morbidity and mortality due to Anaplasma marginale, a tick-borne pathogen of cattle highly endemic in west Africa. In Trial 1, haplotype matched Friesian x Sanga (F1) A. marginale negative calves were allocated to either the experimental group (n = 10) and injected with the synthetic TLR 7 agonist/saponin formulation or to an untreated control group (n = 10). TLR7 agonist/saponin injected calves responded with significantly elevated rectal temperature, enlarged regional lymph nodes, and elevated levels of IL-6 post-injection as compared to control group calves. All calves were then allowed to graze in pasture for natural exposure to tick transmission. All calves in both groups acquired A. marginale, consistent with the high transmission rate in the endemic region. The need for antibiotic treatment, using pre-existing criteria, was significantly lower in the experimental group (odds ratio for not requiring treatment was 9.3, p = 0.03) as compared to the control group. Despite treatment, 6/10 calves in the control group died, reflecting treatment failures that are typical of anaplasmosis in the acute phase, while mortality in the experimental group was 1/10 (odds ratio for survival was 13.5, p = 0.03). The trial was then repeated using 45 Friesian x Sanga calves per group. In Trial 2, the odds ratios for preventing the need for treatment and for mortality in the TLR7 agonist/saponin experimental group versus the control group were 5.6 (p = 0.0002) and 7.0 (p = 0.004), respectively, reproducing the findings of the initial trial. Together these findings demonstrate that innate immune stimulation using a TLR7 agonist formulated with saponin and water-in-oil emulsion provides significant protection against disease caused by tick borne A. marginale in highly susceptible cross-bred cattle, critically important for their potential to increase productivity for smallholder farmers in Africa.

Dexpanthenol exhibits antiapoptotic and anti-inflammatory effects against nicotine-induced liver damage by modulating Bax/Bcl-xL, Caspase-3/9, and Akt/NF-κB pathways.

Chronic tobacco use can lead to liver damage and inflammation due to the accumulation of various toxins in the body. This study aimed to investigate the correlation between the molecular mechanisms of nicotine-induced liver injury, the caspase cascade, and the Akt/NF-κB signaling pathway, as well as the protective effects of dexpanthenol (DEX). Male rats were subjected to intraperitoneal injections of nicotine at a concentration of 0.5 mg/kg/day and/or DEX at a concentration of 500 mg/kg/day for 8 weeks. After the treatment period, liver function tests were conducted on serum samples, and tissue samples were analyzed for protein levels of Akt, NF-κB, Bax, Bcl-xL, Caspase-3, and Caspase-9, along with histopathological changes. Additionally, assessments of oxidative stress markers and proinflammatory cytokines were carried out. Nicotine administration led to elevated levels of IL-6, IL-1β, MDA, TOS, and oxidative stress index, accompanied by decreased TAS levels. Moreover, nicotine exposure reduced the p-Akt/Akt ratio, increased NF-κB, Bax, Caspase-3, and Caspase-9 protein levels, and decreased the antiapoptotic protein Bcl-xL levels. DEX treatment significantly mitigated these effects, restoring the parameters to levels comparable to those of the control group. Nicotine-induced liver injury resulted in oxidative stress, inflammation, and apoptosis, mediated by Bax/Bcl-xL, Caspase-3, Caspase-9, and Akt/NF-κB pathways. Conversely, DEX effectively attenuated nicotine-induced liver injury by modulating apoptosis through NF-κB, Caspase-3, Caspase-9, Bax inhibition, and Bcl-xL activation.

IL-6 signaling accelerates iron overload by upregulating DMT1 in endothelial cells to promote aortic dissection.

Aortic dissection (AD), caused by tearing of the intima and avulsion of the aortic media, is a severe threat to patient life and organ function. Iron is closely related to dissection formation and organ injury, but the mechanism of iron ion transport disorder in endothelial cells (ECs) remains unclear. We identified the characteristic EC of dissection with iron overload by single-cell RNA sequencing data. After intersecting iron homeostasis and differentially expressed genes, it was found that hypoxia-inducible factor-1α (HIF-1α) and divalent metal transporter 1 (DMT1) are key genes for iron ion disorder. Subsequently, IL-6R was identified as an essential reason for the JAK-STAT activation, a classical iron regulation pathway, through further intersection and validation. In in vivo and in vitro, both high IL-6 receptor expression and elevated IL-6 levels promote JAK1-STAT3 phosphorylation, leading to increased HIF-1α protein levels. Elevated HIF-1α binds explicitly to the 5'-UTR sequence of the DMT1 gene and transcriptionally promotes DMT1 expression, thereby increasing Fe2+ accumulation and endoplasmic reticulum stress (ERS). Blocking IL-6R and free iron with deferoxamine and tocilizumab significantly prolonged survival and reduced aortic and organ damage in dissection mice. A comparison of perioperative data between AD patients and others revealed that high free iron, IL-6, and ERS levels are characteristics of AD patients and are correlated with prognosis. In conclusion, activated IL-6/JAK1/STAT3 signaling axis up-regulates DMT1 expression by increasing HIF-1α, thereby increasing intracellular Fe2+ accumulation and tissue injury, which suggests a potential therapeutic target for AD.

Effect of pasak bumi (Eurycoma longifolia Jack), DHA, and seluang fish (Rasbora spp.) on neuroinflammation and neurotransmitter alterations in malnourished rats

Background: Malnutrition has detrimental effects on brain development, leading to neuroinflammatory and neurotransmitter disorders. A nutrient-rich diet is advocated to mitigate these effects. In South Kalimantan, natural resources such as pasak bumi (Eurycoma longifolia Jack.) and seluang fish (Rasbora spp.) are recognized for their potential antioxidant and anti-inflammatory properties. Objective: This study aimed to evaluate the effects of pasak bumi in comparison with seluang fish and DHA on neuroinflammation and neurotransmitter imbalances in malnourished rats. Methods: The study involved dividing malnourished rats into six experimental groups: (1) untreated control, (2) treated with pasak bumi extract, (3) treated with DHA, (4) treated with a combination of DHA and pasak bumi extract, (5) treated with seluang fish, (6) treated with a combination of seluang fish and pasak bumi extract; and a control group of normal rats receiving standard feed and placebo. The primary outcomes measured were levels of IL-6, TNF-α, and serotonin. Results: The study revealed that malnutrition in rats significantly elevated IL-6 and TNF-α levels. Treatments involving pasak bumi extract, both alone and in combination with DHA or seluang fish, reduced IL-6 levels. Similarly, combination of pasak bumi extract and DHA or seluang fish lowered TNF-α levels than single treatment of pasak bumi extract (p &gt; 0.05). All treatments did not reduce the serotonin level. Conclusion: The findings of this study underscore the potent anti-inflammatory capabilities of pasak bumi extract, particularly when combined with DHA or seluang fish, in mitigating the inflammatory response in malnourished rats.

Identification of risk factors for disseminated cryptococcosis in non-hiv patients: a retrospective analysis

ObjectiveThis study aimed to investigate the potential risk factors associated with disseminated cryptococcosis in HIV-negative individuals.MethodsA total of 106 HIV-negative patients with cryptococcal disease were enrolled. The observation group consisted of patients with disseminated cryptococcosis (DC), whereas the control groups included patients with pulmonary cryptococcosis (PC) and cryptococcal meningitis (CM). Univariate and multivariate logistic regression algorithms were used to explore the significant clinical and laboratory characteristics that affect the progression of cryptococcal infections. Finally, receiver operating characteristics (ROC) curves are applied to assess the diagnostic value of identified risk factors.LE: Kindly check the edit made in the title.I agreeResultsOf the 106 patients, 57 were diagnosed with pulmonary cryptococcosis, 22 with cryptococcal meningitis, and 27 with disseminated cryptococcosis. The logistic regression equation included five variables: diabetes, decompensated liver cirrhosis, long-term use of immunosuppressive agents, decreased serum albumin level, and elevated plasma cytokine IL-10 level. The ROC curves showed that albumin (AUC > 0.7), IL-10 (AUC > 0.7) and decompensated liver cirrhosis (AUC > 0.6) have relatively high diagnostic capacity in predicting the progression of Cryptococcus.ConclusionThis study identified elevated IL-10 levels as an independent risk factor for developing disseminated cryptococcosis in the control groups. Furthermore, decompensated liver cirrhosis and decreased serum albumin independently affected the progression of cryptococcosis in the CM and PC groups, respectively.

IL-10 and IFN-γ as markers for early recognition of pediatric systemic lupus erythematosus complicated with macrophage activation syndrome.

To compare the clinical and laboratory characteristics of pediatric-onset systemic lupus erythematosus (pSLE), pSLE with macrophage activation syndrome (MAS), and pSLE with recurrent MAS, and to find biomarkers for the differential diagnosis of these diseases. Demographic, clinical, laboratory and radiological data were analyzed for three groups of patients: 18 cases of pSLE with MAS, 48 age- and sex-matched cases of active pSLE without MAS and 40 age- and sex-matched cases of pSLE with inactive disease. One case of a 9-year-old girl with recurrent MAS as the primary manifestation of SLE also was recorded. IL-10 and IFN-γ levels were significantly higher in pSLE patients with MAS than in pSLE patients without MAS, and were significantly correlated with SLE and MAS laboratory features. Levels of IL-10 > 7.25 pg/ml had a high sensitivity and levels of IFN-γ > 6.7 pg/ml had a high specificity for predicting MAS in pSLE. Constitutional symptoms were evident in the case of recurrent MAS in pSLE, and traditional immunosuppressive therapies were unable to prevent the next MAS episode. Compared with pSLE and pSLE-MAS with a single episode, pSLE with recurrent MAS has different clinical manifestations and responses to treatment, requiring intensive studies to elucidate the underlying pathogenic mechanisms. Elevated serum levels of IL-10 and IFN-γ may be correlated with pSLE with MAS, and can serve as serum biomarkers for pSLE with MAS.

Redox imbalance and inflammation: A link to depression risk in brazilian pesticide-exposed farmers

This study aims to elucidate the mechanisms linking occupational pesticide exposure to depression among rural workers from Maravilha, Brazil. We assessed the mental health, oxidative, and inflammatory profiles of farmers exposed to pesticides (N = 28) and compared them to an urban control group without occupational exposure to pesticides (N = 25). Data on sociodemographic, occupational history, and clinical records were collected. Emotional states were evaluated using the State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory (BDI). Biochemical, hematological, inflammatory, and redox parameters were examined in blood samples from both groups. Results showed educational disparities between groups and unveiled a concerning underutilization of personal protective equipment (PPEs) among farmers. Glyphosate was the predominant pesticide used by farmers. Farmers exhibited higher BDI scores, including more severe cases of depression. Additionally, elevated levels of creatinine, ALT, AST, and LDH were observed in farmers, suggesting potential renal and hepatic issues due to pesticide exposure. Oxidative stress markers, such as increased lipid peroxidation and superoxide dismutase (SOD) activity, along with decreased catalase (CAT) activity and ascorbic acid levels, were noted in the pesticide-exposed group compared to controls. Elevated levels of inflammatory cytokines, particularly IL-1β, IL-6 and TNF-α, were also observed in pesticide-exposed group. Our findings suggest that inflammation, oxidative distress and lower educational levels may be associated with depression in pesticide-exposed farmers. This study highlights the impact of occupational pesticide exposure on the mental health of rural workers. The underuse of PPEs and the link between depressive symptoms, inflammation, and oxidative stress underscore the urgent need for improved safety measures in agricultural practices. Addressing these issues will contribute to a deeper understanding of the intricate relationship between environmental exposures and mental health outcomes.

Patterns of Mannose-Binding Lectin (MBL) responses to &lt;i&gt;Plasmodium falciparum&lt;/i&gt; infections in hyperendemic settings

Background: malaria caused by Plasmodium falciparum remains a significant and major public health concern in Africa, particularly in hyperendemic regions. Recurrent fevers and high quantities of inflammatory mediators in the circulation define the disease's blood stages. By binding to non-self-pathogen oligosaccharide surfaces, Mannose-Binding Lectin (MBL) and lectin complement pathways trigger innate immune processes and contribute to the formation of adaptive immune responses. Methods: in Sudan, we investigated the varied immune response levels of MBL to the different phases of P. falciparum infection in White Nile and Blue Nile states endemic to malaria. And we looked at the interaction of regulatory Interleukin 6 (IL- 6) cytokines on MBL during infection. Our study was based on a total of 108 cases, in which 86 patients (62.0%) were uncomplicated and (17.6%) were severe, all met the diagnostic criteria and were clinically admitted for malaria infections. For the determination of serum MBL and IL-6 levels, a commercial ELISA kit was employed. Results: the analysis of the results revealed significantly elevated levels of MBL and IL-6 in both severe and uncomplicated cases (p&lt;0.001). And MBL average in contrast to residents, Blue Nile patients had high parasitemia (599.9 ng/mL) and this difference was statistically significant (p-value&lt;0.05). The remarkable positive correlation of IL-6 serum levels with MBL among malaria patients and healthy controls (r=0.399, p&lt;0.001) was noted too. Conclusions: according to the findings of this study, patients living in hyperendemic areas exhibit a different MBL response rate and appear to be more homogeneous in proportion to the density of P. falciparum due to parasitemia. In addition, it is also dependent on the regulatory immune mediator IL-6.

Maternal immune activation mediated prenatal chronic stress induces Th17/Treg cell imbalance may relate to the PI3K/Akt/NF-κB signaling pathway in offspring rats

Maternal immune activation (MIA), defined as elevated levels of inflammatory markers beyond the normal range, can occur due to psychological stress, infection, and other disruptions during pregnancy. MIA affects the immune system development in offspring and increases the risk of immune-related disorders. Limited studies have investigated the effects of prenatal stress on offspring's immune system. In this study, pregnant rats were exposed to chronic unpredictable mild stress (CUMS) during pregnancy, involving seven different stressors. We examined the impact of prenatal stress stimuli on the offspring's immune system and observed activation of the PI3K/Akt/NF-κB signaling pathway, resulting in an imbalance of Th17/Treg cells in the offspring's spleen. Our findings revealed increased plasma levels of corticosterone, IL-1β, and IL-6 in female rats exposed to prenatal stress, as well as elevated serum levels of IL-6 and TNF-α in the offspring. Furthermore, we identified a correlation between cytokine levels in female rats and their offspring. Transcriptome sequencing and qPCR experiments indicated differentially expressed mRNAs in offspring exposed to prenatal stress, which may contribute to the imbalance of Th17/Treg cells through the activation of the Gng3-related PI3K/Akt/NF-κB pathway.

Red Ginger's Anti-Anxiety Effect on BALB/c Strain Mice (Mus musculus) Pro-Inflammatory and Anti-Inflammatory Measurements as Anxiety Model

There is a correlation between the occurrence of anxiety and the production of inflammatory mediators, and red ginger rhizome is a well-known herbal product with a high content of phenolic and flavonoid compounds that can be used as anti-inflammatories and antioxidants. The aim of study to evaluate the effect of red ginger as antianxiety in mice (Mus musculus) BALB/c strain by measuring levels of TNF-α, IL-6 and IL-10. Anxiety model mice were carried out by giving treatment with the Forced Swimming Test (FST) for 7 days then assessed by carrying out the Elevated Plus Maze for Mice (EPM) test for one day. After the treatment, the anxiety mice model was made, followed by administration of red ginger ethanol extract therapy for 14 days. The distribution of the experimental animal model groups was divided into control groups (KN, K-, K+) and treatment groups (P, P2, P3).There was a significant difference the decreased of the TNF-α levels at the all of treatment groups with red ginger rhizome extract (P1, P2, P3) compared with the control groups (KN, K-) (p&lt;0.05), the significantly decreased of IL-6 levels in the three doses treatment group (P1, P2, P3) compared to the control group (K-, K+) (p &lt;0.05) and an increase in IL-10 levels in the 50 mg treatment group compared to group K -, statistically not significant (p&gt;0.05).In overall, this study suggests that FST stimulation will create anxiety symptoms and behavior as well as impact cytokine levels, namely elevated levels of TNF-α and IL-6. Giving red ginger ethanol extract has the potential to be researched further for reducing anxiety symptoms because it can block pro-inflammatory cytokines by significantly decreased levels of TNF-α, IL-6, and increased IL-10 cytokines a brief abstract about your paper’s subject of study.

Comparison of Oral Health and Salivary Biomarkers in Children with Juvenile Idiopathic Arthritis and Healthy Individuals.

This study examines the effects of juvenile idiopathic arthritis (JIA) on the oral health and detectability of inflammatory biomarkers IL-17, tumour necrosis factor-alpha (TNF-α) and total antioxidant status (TAS) in the saliva of children with JIA. This study included 117 participants (39 patients with JIA and 78 systemically healthy subjects aged 8-12 years). Demographic data, responses to an oral health-related questionnaire, saliva samples, periodontal parameters [plaque index (PI), gingival index (GI) and bleeding on probing (BOP)] and dental recordings [facial profile (FP) and dental occlusion relationship (DOR)] were obtained. Enzyme-linked immunosorbent assays were used to determine the levels of salivary IL-17, TNF-α and TAS. The Caries Assessment Spectrum and Treatment (CAST) index, FP and DOR distributions did not change between groups (P > 0.05). JIA patients had more temporomandibular joint (TMJ) discomfort than gingivitis patients and healthy subjects (P < 0.05). JIA patients had greater salivary IL-17 levels than healthy subjects (P < 0.05). The healthy group's TAS was higher than that of the JIA and gingivitis groups (P < 0.05). Saliva TNF-α levels were similar between groups (P > 0.05). PI, GI, BOP and TNF-α were positively associated with salivary IL-17 (P < 0.001). Elevated salivary IL-17 and TAS levels could be used as biological markers for discriminating the clinical health status of children with JIA and gingivitis.

TRPV1-positive sensory nerves and neuropeptides are involved in epidermal barrier repair after tape stripping in mice

The integumentary system of the skin serves as an exceptional protective barrier, with the stratum corneum situated at the forefront. This outermost layer is composed of keratinocytes that biosynthesize filaggrin (encoded by the gene Flg), a pivotal constituent in maintaining skin health. Nevertheless, the precise role of sensory nerves in restoration of the skin barrier after tape stripping-induced epidermal disruption, in contrast to the wound-healing process, remains a tantalizing enigma. This study aimed to elucidate the cryptic role of sensory nerves in repair of the epidermal barrier following tape stripping-induced disruption. Through the implementation of resiniferatoxin (RTX)-treated denervation mouse model, we investigated the kinetics of barrier repair after tape stripping and performed immunophenotyping and gene expression analysis in the skin or dorsal root ganglia (DRG) to identify potential neuropeptides. Furthermore, we assessed the functional impact of candidates on the recovery of murine keratinocytes and RTX-treated mice. Ablation of TRPV1-positive sensory nerve attenuated skin barrier recovery and sustained subcutaneous inflammation, coupled with elevated IL-6 level in ear homogenates after tape stripping. Expression of the keratinocyte differentiation marker Flg in the ear skin of RTX-treated mice was decreased compared with that in control mice. Through neuropeptide screening, we found that the downregulation of Flg by IL-6 was counteracted by somatostatin or octreotide (a chemically stable somatostatin analog). Furthermore, RTX-treated mice given octreotide exhibited a partial improvement in barrier recovery after tape stripping. Sensory neurons expressing TRPV1 play an indispensable role in restoring barrier function following epidermal injury. Our findings suggest the potential involvement of somatostatin in restoring epidermal repair after skin injury.

Evaluation of causal associations between interleukin-18 levels and immune-mediated inflammatory diseases: a Mendelian randomization study

BackgroundAltered interleukin (IL)-18 levels are associated with immune-mediated inflammatory diseases (IMIDs), but no studies have investigated their causal relationship. This study aimed to examine the causal associations between IL-18 and IMIDs.MethodsWe performed a two-sample Mendelian randomization (MR) analysis. Genetic variants were selected from genome-wide association study datasets following stringent assessments. We then used these variants as instrumental variables to estimate the causal effects of IL-18 levels on the risk of developing five common IMIDs: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ankylosing spondylitis (AS), and psoriasis. We used the inverse variance-weighted (IVW) method as the primary analysis, with sensitivity analyses performed to avoid potential bias. Reverse-direction MR analyses were performed to rule out the possibility of reverse associations.ResultsWe found that genetically determined higher circulating IL-18 levels were causally associated with a higher risk for SLE (PIVW = 0.009; OR, 1.214; 95% CI, 1.049 − 1.404) and IBD (PIVW < 0.001; OR, 1.142; 95% CI, 1.062 − 1.228), but found no significant associations of IL-18 with RA (PIVW = 0.496; OR, 1.044; 95% CI, 0.923 − 1.180), AS (PIVW = 0.021; OR, 1.181; 95% CI, 1.025 − 1.361), or psoriasis (PIVW = 0.232; OR, 1.198; 95% CI, 0.891 − 1.611). In the reverse direction, no causal relationship existed between SLE or IBD and IL-18 levels. Globally, sensitivity studies using alternative MR methods supported the results that were robust and reliable. The Cochran’s Q test, MR-Egger intercept, and MR-Pleiotropy RESidual Sum and Outlier excluded the influence of heterogeneity, horizontal pleiotropy, and outliers.ConclusionsWe have demonstrated that elevated IL-18 levels increase the risk of SLE and IBD but not RA, AS, or psoriasis. The results enhanced our understanding of IL-18 in the pathology of IMIDs.

The autoinflammation-associated NLRC4V341A mutation increases microbiota-independent IL-18 production but does not recapitulate human autoinflammatory symptoms in mice.

Autoinflammation with infantile enterocolitis (AIFEC) is an often fatal disease caused by gain-of-function mutations in the NLRC4 inflammasome. This inflammasomopathy is characterized by macrophage activation syndrome (MAS)-like episodes as well as neonatal-onset enterocolitis. Although elevated IL-18 levels were suggested to take part in driving AIFEC pathology, the triggers for IL-18 production and its ensuing pathogenic effects in these patients are incompletely understood. Here, we developed and characterized a novel genetic mouse model expressing a murine version of the AIFEC-associated NLRC4V341A mutation from its endogenous Nlrc4 genomic locus. NLRC4V341A expression in mice recapitulated increased circulating IL-18 levels as observed in AIFEC patients. Housing NLRC4V341A-expressing mice in germfree (GF) conditions showed that these systemic IL-18 levels were independent of the microbiota, and unmasked an additional IL-18-inducing effect of NLRC4V341A expression in the intestines. Remarkably, elevated IL-18 levels did not provoke detectable intestinal pathologies in NLRC4V341A-expressing mice, even not upon genetically ablating IL-18 binding protein (IL-18BP), which is an endogenous IL-18 inhibitor that has been used therapeutically in AIFEC. In addition, NLRC4V341A expression did not alter susceptibility to the NLRC4-activating gastrointestinal pathogens Salmonella Typhimurium and Citrobacter rodentium. As observed in AIFEC patients, mice expressing a murine NLRC4V341A mutant show elevated systemic IL-18 levels, suggesting that the molecular mechanisms by which this NLRC4V341A mutant induces excessive IL-18 production are conserved between humans and mice. However, while our GF and infection experiments argue against a role for commensal or pathogenic bacteria, identifying the triggers and mechanisms that synergize with IL-18 to drive NLRC4V341A-associated pathologies will require further research in this NLRC4V341A mouse model.

Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment

As the heterogeneity of symptoms is increasingly recognized among long-COVID patients, it appears highly relevant to study potential pathophysiological differences along the different subtypes. Preliminary evidence suggests distinct alterations in brain structure and systemic inflammatory patterns in specific groups of long-COVID patients.To this end, we analyzed differences in cortical thickness and peripheral immune signature between clinical subgroups based on 3 T-MRI scans and signature inflammatory markers in n = 120 participants comprising healthy never-infected controls (n = 30), healthy COVID-19 survivors (n = 29), and subgroups of long-COVID patients with (n = 26) and without (n = 35) cognitive impairment according to screening with Montreal Cognitive Assessment. Whole-brain comparison of cortical thickness between the 4 groups was conducted by surface-based morphometry.We identified distinct cortical areas showing a progressive increase in cortical thickness across different groups, starting from healthy individuals who had never been infected with COVID-19, followed by healthy COVID-19 survivors, long-COVID patients without cognitive deficits (MoCA ≥ 26), and finally, long-COVID patients exhibiting significant cognitive deficits (MoCA < 26). These findings highlight the continuum of cortical thickness alterations associated with COVID-19, with more pronounced changes observed in individuals experiencing cognitive impairment (p < 0.05, FWE-corrected). Affected cortical regions covered prefrontal and temporal gyri, insula, posterior cingulate, parahippocampal gyrus, and parietal areas. Additionally, we discovered a distinct immunophenotype, with elevated levels of IL-10, IFNγ, and sTREM2 in long-COVID patients, especially in the group suffering from cognitive impairment.We demonstrate lingering cortical and immunological alterations in healthy and impaired subgroups of COVID-19 survivors. This implies a complex underlying pathomechanism in long-COVID and emphasizes the necessity to investigate the whole spectrum of post-COVID biology to determine targeted treatment strategies targeting specific sub-groups.

Primary Effusion Lymphoma Prognostic Score (PEL-PS): A Validated International Prognostic Score in HIV-Associated Primary Effusion Lymphoma

Background: Primary effusion lymphoma (PEL) is a rare, B cell non-Hodgkin lymphoma (NHL) caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8, that is most common in people with HIV. It has a unique natural history among NHL presenting as malignant body cavity effusions, accompanying inflammatory signs and symptoms, and 80% of tumors are also EBV positive. PEL has poor survival compared with other HIV-associated lymphomas with fewer than 50% of patients alive 3 years after diagnosis. The International Prognostic Index (IPI) has not been validated in PEL due to its rarity. ECOG performance status, levels of interleukin (IL)-6, IL-10, and EBV positivity of the tumor have been shown to be prognostic in small cohorts of patients with PEL, but these factors have not been validated. In a large international cohort, we sought to develop and validate a prognostic model in HIV-associated PEL. Methods: We collected demographic and clinical data from patients with HIV-associated PEL who received first-line anthracycline-containing chemotherapy. The training set used to develop the predictive model was identified from patients treated in the HIV and AIDS Malignancy Branch at the National Cancer Institute (NCI) in the United States and Chelsea and Westminster Hospital (CWH) in the United Kingdom from 2000-2022. We performed univariate Kaplan-Meier analyses to determine prognostic factors of overall survival (OS). Factors with unadjusted p-values &amp;lt;0.10 were candidates for inclusion in the Cox proportional hazards model. We applied backward and stepwise selection to determine independent factors for inclusion in the final Cox model. The factors identified in the Cox model were able to form two groups of patients who were predicted to have good or poor survival. The factors included in the Cox model and the groupings formed were then applied to a validation set identified from patients with HIV-associated PEL treated with first-line anthracycline-containing chemotherapy at the Hôpital Saint-Louis in France over the same period. T cell counts and peripheral blood KSHV viral loads were not measured uniformly across institutions and could not be evaluated in the Cox model. Results: For the training cohort, we identified 59 patients with PEL treated with first-line anthracycline-containing chemotherapy at NCI and CWH. The median OS was 10.6 years and not statistically different between institutions (P=0.27). In univariate analysis, 5 factors were statistically negative prognostic factors: ECOG 3-4, hemoglobin &amp;lt;8 g/dL, albumin ≤2 g/dL, platelets &amp;lt;135 K/L, and IPI 4-5. Two factors were statistically positive prognostic factors: extracavitary only disease and EBV + tumors. In the multivariable Cox model, only 2 factors, ECOG ≥3 [P=0.007; hazard ratio (HR)=4.0 (95% CI: 1.5-11.1)] and hemoglobin &amp;lt;8 g/dL [P=0.006; HR=3.8 (95% CI: 1.5-9.7)] were jointly associated with lower survival probability. After forming groups based on the permutations of hemoglobin and ECOG, a scoring system was devised using patients with no negative prognostic factors (score 0: hemoglobin ≥8 g/dL and ECOG ≤2) versus patients with 1-2 negative prognostic factors (score 1: hemoglobin &amp;lt;8 g/dL and/or ECOG ≥3) resulting in a median OS of 10.6 years (95% CI: 10.6-not estimable) versus 0.8 years (95% CI: 0.3-2.8 years), p&amp;lt;0.0001, respectively. The validation cohort was very similar to the training cohort in terms of patient and disease characteristics. When we applied the multivariable model to the 58 patients from the validation cohort, ECOG and hemoglobin jointly predicted OS, validating the prognostic model [ECOG ≥3: P=0.0005; HR=15.6 (95% CI: 3.3-73.5) and hemoglobin &amp;lt;8 g/dL: P=0.04; HR=2.5 (95% CI: 1.05-5.8)]. Median OS in patients with score 0 was 16.9 years (95% CI:8.7-16.9) versus 0.6 years (95% CI: 0.3-1.0) in those with score 1. Conclusion: Using the largest international cohort of patients with HIV-associated PEL ever evaluated, we developed and validated the PEL-PS, which is easily implementable in any clinical setting using ECOG and hemoglobin. Low hemoglobin may be a surrogate marker for KSHV-associated inflammation and elevated IL-6 levels, and this association should be evaluated further. Patients with poor prognosis identified by the PEL-PS may benefit from novel therapies currently under investigation in PEL, such as immunomodulatory drugs, anti-CD38 monoclonal antibodies, and anti-PD-1 agents.