Inflammatory Profile Research Articles

Integration of epidemiological and blood biomarker analysis links haem iron intake to increased type 2 diabetes risk.

Dietary haem iron intake is linked to an increased risk of type 2 diabetes (T2D), but the underlying plasma biomarkers are not well understood. We analysed data from 204,615 participants (79% females) in three large US cohorts over up to 36 years, examining the associations between iron intake and T2D risk. We also assessed plasma metabolic biomarkers and metabolomic profiles in subsets of 37,544 (82% females) and 9,024 (84% females) participants, respectively. Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk, with a multivariable-adjusted hazard ratio of 1.26 (95% confidence interval 1.20-1.33; P for trend <0.001) comparing the highest to the lowest quintiles. Haem iron accounts for significant proportions of the T2D risk linked to unprocessed red meat and specific dietary patterns. Increased haem iron intake correlates with unfavourable plasma profiles of insulinaemia, lipids, inflammation and T2D-linked metabolites. We also identify metabolites, including L-valine and uric acid, potentially mediating the haem iron-T2D relationship, highlighting their pivotal role in T2D pathogenesis.

Indoor air pollution impacts cardiovascular autonomic control during sleep and the inflammatory profile

The present study explores the modifications of cardiovascular autonomic control (CAC) during wake and sleep time and the systemic inflammatory profile associated with exposure to indoor air pollution (IAP) in a cohort of healthy subjects.Twenty healthy volunteers were enrolled. Indoor levels of fine particulate matter (PM2.5), nitrogen dioxide (NO2) and volatile organic compounds (VOCs) were monitored using a portable detector for 7 days. Together, a 7-day monitoring was performed through a wireless patch that continuously recorded electrocardiogram, respiratory activity and actigraphy. Indexes of CAC during wake and sleep time were derived from the biosignals: heart rate and low-frequency to high-frequency ratio (LF/HF), index of sympathovagal balance with higher values corresponding to a predominance of the sympathetic branch. Cyclic variation of heart rate index (CVHRI events/hour) during sleep, a proxy for the evaluation of sleep apnea, was assessed for each night. After the monitoring, blood samples were collected to assess the inflammatory profile. Regression and correlation analyses were performed.A positive association between VOC exposure and the CVHRI (Δ% = +0.2% for 1 μg/m3 VOCs, p = 0.008) was found. The CVHRI was also positively associated with LF/HF during sleep, thus higher CVHRI values corresponded to a shift of the sympathovagal balance towards a sympathetic predominance (r = 0.52; p = 0.018). NO2 exposure was positively associated with both the pro-inflammatory biomarker TREM-1 and the anti-inflammatory biomarker IL-10 (Δ% = +1.2% and Δ% = +2.4%, for 1 μg/m3 NO2; p = 0.005 and p = 0.022, respectively).The study highlights a possible causal relationship between IAP exposure and higher risk of sleep apnea events, associated with impaired CAC during sleep, and a pro-inflammatory state counterbalanced by an increased anti-inflammatory response in healthy subjects. This process may be disrupted in vulnerable populations, leading to a harmful chronic pro-inflammatory profile. Thus, IAP may emerge as a critical and often neglected risk factor for the public health that can be addressed through targeted preventive interventions.

Androgen deprivation exacerbates AD pathology by promoting the loss of microglia in an age-dependent manner

AimsMicroglial cells are integral to the pathogenesis of Alzheimer's disease (AD). The observed sex disparity in AD prevalence, with a notable predominance in women, implies a potential influence of sex hormones, such as androgens, on disease mechanisms. Despite this, the specific effects of androgens on microglia remain unclear. This study is designed to delineate the interplay between androgens and the survival and inflammatory profile of microglial cells, as well as to explore their contribution to the progression of AD. Methods and key findingsTo create a chronic androgen deficiency model, 3-month-old wild-type (WT) mice and APP/PS1 mice underwent bilateral orchiectomy (ORX), with age-matched sham-operated controls. Cognitive and memory were evaluated at 5 and 12 months, paralleled by assessments of amyloid-beta (Aβ) and microglial morphology in hippocampal and cortical areas. The ORX treatment in mice resulted in diminished microglial populations and morphological alterations, alongside an increase in Aβ plaques and a concomitant decline in cognitive performance that exacerbated over time. In vitro, dihydrotestosterone (DHT) was found to stimulate microglial proliferation and ameliorate Aβ1–42-induced apoptosis. SignificanceThese findings suggested that androgens may exert a protective role, maintaining the normal proliferation and functionality of microglial cells. This preservation could potentially slow the progression of AD. As a result, our study provided a conceptual framework for the development of novel therapeutic strategies for AD.

Serum selenium level and its relation with inflammatory profile in hemodialysis children

Introduction: Chronic kidney disease (CKD) is described by structural or functional defects staying for three months. End-stage kidney disease (ESKD) patients undergoing renal replacement therapy (RRT) face complications and increased susceptibility to infections due to their compromised immune system. In addition, malnutrition and chronic inflammatory conditions are prevalent in CKD patients. Selenium, an essential trace element, plays a crucial role as a cofactor in antioxidant enzymes like glutathione peroxidase (GPX), contributing to vascular endothelial function. Selenium deficiency in patients with ESKD may intensify oxidative stress, increase susceptibility to cardiovascular complications, and impact mortality rates. Despite the significance of selenium in this context, studies on its levels in children undergoing hemodialysis (HD) are limited. Objectives: This study assessed serum selenium levels in children undergoing HD, compared with healthy children. Furthermore, we sought to establish correlations between selenium levels and inflammatory profiles in the HD group. Patients and Methods: An observational cross-sectional study was conducted with 30 pediatric patients with ESKD undergoing HD (HD group) and 50 healthy children (control group) in Tehran, Iran. Blood samples were collected from both groups, and serum selenium levels along with inflammatory markers were analyzed. The inclusion criteria encompassed pediatric ESKD patients undergoing HD for at least six months without recent inflammation or infections. The exclusion criteria comprised active infections, immunodeficiency syndromes, and corticosteroid therapy. Statistical analyses were performed using SPSS statistics. Results: Significant differences were observed in serum selenium levels between the HD and control groups (P=0.039). Correlation analysis disclosed a direct relationship among selenium levels and participant age (r = 0.235, P=0.036), with no significant difference between genders. Notably, significant correlations were found between selenium levels and erythrocyte sedimentation rate (ESR) and platelet-to-lymphocyte ratio (PLR). In contrast, no significant correlation between selenium levels and other inflammatory profiles was established. Conclusion: This study underscores the importance of assessing serum selenium levels in pediatric ESKD patients undergoing HD. Understanding the interplay between selenium deficiency and inflammatory profiles can inform interventions aimed at improving outcomes and reducing complications in this vulnerable population. Further researches are necessary to explain these associations and to explore possible therapeutic interventions.

BV2-derived extracellular vesicles modulate microglia inflammatory profile, neuronal plasticity, and behavioural performances in late adult mice

BackgroundDuring aging, both the brain and the immune system undergo a progressive impairment of physiological functions. Microglia, the immunocompetent cells of the central nervous system, shift towards a chronic mild inflammatory state that impacts brain homeostasis. Extracellular vesicles (EVs) released by microglia transport packages of molecular information that mirror the inflammatory status of donor cells and modulate the inflammatory phenotype of recipient microglia and other cell types. ResultsWe demonstrated that intranasal administration of EVs derived from microglial-like BV2 cells to late adult mice (16–20 months of age) shifts microglia toward a “juvenile” morphology affecting their inflammatory profile. Mice treated with BV2-derived EVs have a reduction of anxiety-like behavior and an increased spatial learning, with sex-dependent differences. Further, BV2-derived EVs increased neuronal plasticity both in male and female mice. These findings suggest the involvement of microglial cells in vesicles-mediated anti-aging effect. ConclusionsOur data indicate that BV2-derived EVs could represent a resource to slow down age-dependent inflammation in the mouse brain.

HIV infection is associated with compromised tumor microenvironment adaptive immune reactivity in Hodgkin lymphoma

AbstractThe impact of HIV infection on the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL), one of the most common comorbidities after HIV infection, is not well understood. Here, we have used multiplexed immunofluorescence and spatial transcriptomic analysis to dissect the impact of viral infections (Epstein-Barr virus [EBV] and HIV/EBV) on cHL TME. HIV−EBV+ cHL TME was characterized by higher cell densities of CD8high T cells coexpressing inhibitory receptors (PD-1 and TIGIT), macrophage subsets, and an in situ inflammatory molecular profile associated with increased expression of T-cell receptor (TCR) and B-cell receptor cell signaling pathways than HIV−EBV− cHL TME. Compared with HIV−EBV+, HIV+EBV+ cHL TME was characterized by significantly less CD8high T cells coexpressing PD-1 and TIGIT, a profile concomitant with significantly increased cell densities of CD155high neoplastic cells. Significant downregulation of in situ TCR signaling and upregulation of extracellular matrix reorganization pathways were found in HIV+EBV+ cHL TME, in line with an altered topological organization of CXCL13 and heparan sulfate, an extracellular matrix glycosaminoglycan. Our data reveal the complexity of the cellular and molecular composition of cHL TME in the presence of viral infections, with possible implications for combinatorial immunotherapies. Furthermore, the data suggest specific molecular targets and pathways for further investigation that could improve our understanding of possible mechanistic links between HIV and lymphomagenesis.

Functional and metabolic effects of omega-3 polyunsaturated fatty acid supplementation and the role of β-hydroxy-β-methylbutyrate addition in chronic obstructive pulmonary disease: A randomized clinical trial

IntroductionShort-term (4 weeks) supplementation with n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has recently been shown to improve protein metabolism in a dose dependent way in normal weight patients with Chronic Obstructive Pulmonary Disease (COPD). Furthermore, EPA/DHA supplementation was able to increase extremity lean soft tissue but not muscle function. No studies are available combining n-3 PUFAs and the leucine metabolite β-hydroxy-β-methylbutyrate (HMB) supplementation in chronic clinical conditions. Whether adding HMB to daily EPA/DHA supplementation for 10 weeks enhances muscle and brain health, daily functional performance, and quality of life of patients with COPD by further improving their protein and amino acid homeostasis remains unknown. MethodsPatients with COPD (GOLD: II-IV, n=46) received daily for 10 weeks, according to a randomized double-blind placebo-controlled three-group design, EPA/DHA (n=16), EPA/DHA to which HMB was added (n=14), or placebo (n=16). The daily dose of 2.0 g of EPA/DHA or soy + corn oil as the placebo was provided via gel capsules, and 3.0 g of Ca-HMB or maltodextrin as placebo as powders. At pre- and post-intervention, a pulse mixture of multiple amino acids was administered to measure postabsorptive net protein breakdown (netPB as primary endpoint) and whole body production (WBP) and conversion rates of the amino acids. As secondary endpoints, lean soft tissue, and fat mass were assessed by dual-energy X-ray absorptiometry, upper and lower muscle function by handgrip and single leg isokinetic dynamometry, brain (cognitive, wellbeing) health by assessments, daily functional performance by measuring 6-minute walk distance, 4-meter gait speed, and postural balance, and quality of life by questionnaire. Plasma enrichments and concentrations were analyzed by LC-MS/MS, and systemic inflammatory profile and metabolic hormones by Luminex. ResultsHMB + EPA/DHA but not EPA/DHA supplementation increased postabsorptive netPB (p=0.028), and WBPs of glutamine (p=0.024), taurine (p=0.039), and tyrosine (p=0.036). Both EPA/DHA and HMB + EPA/DHA supplementation resulted in increased WBP of phenylalanine (p<0.05). EPA/DHA but not HMB + EPA/DHA was able to increase WBP of arginine (p=0.030), citrulline (p=0.008), valine (p=0.038), and conversion of citrulline to arginine (p=0.009). Whole body and extremity fat mass were reduced after HMB + EPA/DHA supplementation only, whereas lean soft tissue was increased after EPA/DHA (p=0.049) and HMB + EPA/DHA (p=0.073). No other significant findings were observed. Reductions in several proinflammatory cytokines were observed in the HMB + EPA/DHA group including IL-2, IL-17, IL-6, IL-1 receptor antagonist, IL-12P40, and TNF-β (p<0.05). ConclusionsTen weeks of supplementation with 2 g of EPA/DHA daily is sufficient to induce muscle gain in COPD but HMB is needed to induce fat loss. Whether HMB is solely responsible for the fat mass loss or has a synergistic effect with EPA/DHA remains unclear. The increase in net protein breakdown observed with HMB + EPA/DHA supplementation may not indicate harmful muscle catabolism but rather a beneficial enhanced protein turnover cycling associated with increased lean soft tissue. Clinical Trial RegistryClinicalTrials.gov; NCT03796455

Efficacy of pentoxifylline for the treatment of bipolar I/II patients with treatment-resistant depression: A proof-of-concept, randomized, double-blind, placebo-controlled trial

BackgroundImmune dysregulation can play a role in depression pathophysiology, and immunological antagonists can improve depressive symptoms in treatment-resistant bipolar depression (TRD) patients according to studies. ObjectiveTo evaluate the anti-depressant effects of the anti-inflammatory drug, pentoxifylline (PTX) in TRD bipolar I/II adult subjects. MethodsThis 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at Hawler Psychiatric Hospital and Private Clinic in Erbil, Iraq. Participants were confirmed as being qualified for bipolar I/II depression based on DSM-5 criteria. Data were analyzed using modified intent-to-treat analysis. ResultsThere were no significant differences between the two groups in Hamilton Rating Scale for Depression-17 (HAM-D-17) scores (χ2=1.9, P =.48) or a significant time × treatment interaction (χ2=7.1, P=.54). Nevertheless, a significant effect of time was observed with both groups’ reduction in HAM-D-17 scores from the start to the endpoint (χ2= 2.11, P=.002). Besides, a significant time × treatment × CRP interaction was found (χ2=3.1, P=0.016), where there was more reduction in HAM-D-17 score in PTX-treated subjects with CRP> 7.1 mg/L. The response rate difference between PTX and the placebo group did not reach a significance level (χ2=0.84, p=0.43). Furthermore, serum concentrations of TNF-α, CRP, and IL-6 significantly reduced at week 12 in the PTX group (P=.007,.04, and <.001, respectively). ConclusionThe current proof of concept study found that in terms of overall anti-depressant effectiveness in bipolar patients with TRD, PTX is not superior to placebo. However, it may improve depressive mood in a subpopulation of subjects with a higher pretreatment inflammatory profile.

A transdiagnostic and diagnostic-specific approach on inflammatory biomarkers in eating disorders: A meta-analysis and systematic review

Eating disorders (EDs) are severe mental illnesses with a multifactorial etiology and a chronic course. Among the biological factors related to pathogenesis and maintenance of EDs, inflammation acquired growing scientific interest. This study aimed to assess the inflammatory profile of EDs, focusing on anorexia nervosa, bulimia nervosa, and including for the first time binge eating disorder. A comprehensive research of existing literature identified 51 eligible studies for meta-analysis, comparing levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), osteoprotegerin (OPG), soluble receptor activator of nuclear factor kappa-B ligand (sRANKL), interleukin-1β (IL-1β), and interleukin-10 (IL-10) between patients with EDs and healthy controls (HCs). The systematic review explored other inflammatory biomarkers of interest, which did not meet the meta-analysis criteria. Results revealed significantly elevated levels of TNF-α, OPG, sRANKL, and IL-1β in patients with EDs compared to HCs. Additionally, the results highlighted the heterogeneity of inflammatory state among patients with EDs, emphasizing the need for further research into the association between inflammatory biomarkers and psychopathological correlates. This approach should transcend categorical diagnoses, enabling more precise subcategorizations of patients.Overall, this study contributed to the understanding of the inflammatory pathways involved in EDs, emphasizing potential implications for diagnosis, staging, and targeted interventions.

Better clinical outcomes and lower triggering of inflammatory cytokines for allogeneic hematopoietic cell transplant recipients treated in home care versus hospital isolation - the Karolinska experience.

After allogeneic hematopoietic cell transplantation (Allo-HCT) and conditioning, patients are typically placed in isolated hospital rooms to prevent neutropenic infections. Since 1998, we've offered an alternative: home care for patients living within a one to two-hour drive of the hospital. In Sweden this approach includes daily visits by an experienced nurse and daily phone consultations with a unit physician. When necessary, patients receive transfusions, intravenous antibiotics, and total parenteral nutrition at home. Our initial study report compared 36 home care patients with 54 hospital-treated controls. Multivariate analysis found that home care patients were discharged earlier to outpatient clinics, required fewer days of total parenteral nutrition, had less acute graft-versus-host disease (GVHD) grade II-IV, and lower transplantation-related mortality (TRM) and lower costs. Long-term follow-up showed similar chronic GVHD and relapse rates in both groups, with improved survival rates in the home care group. A subsequent comparison of 146 home care patients with hospital-treated controls indicated that home care and longer home stays were associated with lower grades of acute GVHD. Home care was found to be safe and beneficial for children and adolescents. Over two decades, 252 patients received home care post-Allo-HCT without any fatalities at-home. Ten-year outcomes showed a 14% TRM and a 59% survival rate. In 2020, an independent center confirmed the reduced risk of acute GVHD grades II-IV for patients treated in home care. Here, we report for the first time that home care patients also demonstrate a less inflammatory systemic cytokine profile. We found higher levels of IFN-γ, IL-2, IL-5, IL-13, GM-CSF, and G-CSF, but lower VEGF in hospital-treated patients, which may contribute to acute GVHD grades II-IV. In conclusion, home-based treatment following Allo-HCT yields multiple promising clinical outcomes and improved systemic inflammatory markers, which may contribute to less development of life-threatening GVHD.

Fibroblast growth-factor 23-Klotho axis is associated with systemic inflammation and myokine profile in children with chronic kidney disease.

Chronic kidney disease is linked to a disturbed fibroblast growth factor-23 (FGF23)-Klotho axis and an imbalance between myostatin and insulin-like growth factor-1 (IGF-1) expression. This cross-sectional study investigates the association of the FGF23-Klotho axis and myokine profile with serum interleukin-6 (IL-6) and their interactions in pediatric patients. Serum calcium, phosphorus, 25-hydroxyvitamin D, parathormone, c-terminal FGF23, a-Klotho, myostatin, follistatin, IGF-1, and IL-6 were measured in 53 patients with GFR < 60ml/min/1,73m2. Myostatin to lean mass (LM) and to IGF-1 ratios were calculated. IL-6 level > 3rd quartile was considered as high. Myostatin, IGF-1, and follistatin were correlated to LM (rs = 0.513, p < 0.001, rs = 0.652, p < 0.001, rs=-0.483, p < 0.001). Myostatin and follistatin were correlated to IGF-1 (rs = 0.340, p = 0.014, rs=-0.385, p = 0.005). Myostatin/LM but not myostatin or myostatin/IGF-1 ratio was significantly higher in CKD 5D patients (p = 0.001,p = 0.844, p = 0.111). Among mineral bone parameters, lnFGF23 was correlated to lnIL-6 (rs = 0.397, p = 0.004) and associated with high IL-6 (OR 1.905, 95% CI 1.023-3.548). Among myokines, myostatin/IGF-1 ratio was correlated to lnIL-6 (rs = 0.395, p = 0.004) and associated with high IL-6 (OR 1.113, 95% CI 1.028-1.205). All associations were adjusted to CKD stage. Myostatin was correlated to lnFGF23 (rs = 0.331, p = 0.025) and myostatin/IGF-1 ratio to lnKlotho (rs=-0.363, p = 0.013), after adjustment for CKD stage, lnIL-6 and other mineral bone parameters. In pediatric CKD, FGF23 and myostatin/IGF-1 ratio are associated with IL-6, indicating a link between systemic inflammation, mineral bone, and myokine disorders. The correlations between myostatin and FGF23 and between myostatin/IGF-1 and Klotho suggest an interaction between mineral bone and muscle metabolism.

Preoperative vagal activity predicts clinical outcomes after total knee replacement.

Total knee replacement (TKR) surgery carries with it significant surgical trauma and activates complex inflammatory pathways, which initially assist healing. However, impaired regulation of inflammatory pathways can cause tissue damage and postoperative complications. The vagus nerve regulates inflammation, the activity of which is indexed by heart-rate variability (HRV), which predicts postoperative pain, longer hospitalization and improved recovery during the postoperative period. The present study examined the relationship between presurgical HRV, inflammation and complications after TKR. The present study assessed data from 41 patients undergoing TKR. A retrospective design was used, where preoperative electrocardiograms were scanned to determine HRV. Outcome measures included inflammation [C-reactive protein (CRP) levels] over four postoperative days, length of stay (LOS), and complications. Preoperative HRV predicted the trajectory of postoperative CRP levels. The low HRV group demonstrated higher overall postoperative CRP and a longer time to recover than patients with high HRV. Furthermore, the magnitude of inflammatory decline between postoperative days two and four was associated with LOS. However, HRV did not predict postoperative complications. In conclusion, patients with lower presurgical vagal activity had a worse postoperative inflammatory profile than those with high vagal tone. In the age of personalized medicine, such findings may have implications for identifying and preparing patients before surgery.

Resolving Resident Colonic Muscularis Macrophage Diversity and Plasticity During Colitis.

Immune cell populations in the intestinal muscularis propria during colitis are poorly resolved. Maintaining homeostasis in this niche is critical, highlighted by the poorer prognosis of inflammatory bowel disease associated with muscularis propria inflammation. This study utilizes single-cell RNA sequencing to survey the immune cell populations within the muscularis propria of normal colon and dextran sodium sulfate-induced colitis. Findings are validated by immunohistochemistry, flow cytometry and cell-lineage tracing in vivo, and in vitro assays with muscularis macrophages (MMφ). In naïve conditions, transcriptional duality is observed in MMφs with 2 major subpopulations: conventional resident Cx3cr1+ MMφs and Lyve1+ MMφs. The Lyve1+ population is phagocytic and expresses several known MMφ markers in mouse and human, confirming their identity as a bona fide MMφ subset. Single-cell transcriptomics indicate that resident MMφs are retained during colitis and exhibit plasticity toward an inflammatory profile. Lyve1+ MMφs, which express anti-inflammatory marker CD163, are absent during colitis, as confirmed by flow cytometry. In contrast, lineage tracing finds that resident Cx3cr1+ MMφs remain during colitis and are not completely replaced by the inflammatory infiltrating monocytes. In vitro studies provide biological evidence of the plasticity of resident Cx3cr1+ MMφs in response to lipopolysaccharide (LPS), mirroring transcriptional observations in vivo of their inflammatory plasticity. Potential markers for colitic MMφs, validated in animal models and in individuals with ulcerative colitis, are identified. Our findings contribute to the understanding of the immune system in the muscularis propria niche during colitis by resolving the heterogeneity and origins of colitic MMφs.

Cytokine profiles and their roles in development of provoked vulvodynia

Provoked, localized, vulvodynia (PVD) is the main subtype of vulvodynia. Although the etiology of PVD is still a topic of debate, inflammation caused by cytokines responding to a dysregulated microbiome is one of the leading proposed theories. Therefore, the purpose of our study is to further explore the cytokine profiles in the study group with PVD using multiplex immunoassays based on electrochemiluminescence. We compared a panel of 26 distinct cytokines levels in the study group with PVD (n = 23) to the control group (n = 18) and cytokine concentrations were measured using MESO QuickPlex SQ 120 instrument with 5 different multiplex assays. Statistical analysis used the Mann-Whitney U test, two-sided p-values, and a significance level of α = 0.05. Differences in cytokine concentrations are described as negligible, small, medium, or large based on Cliff’s δ. Concentrations of three cytokines were significantly lower in the PVD group: a large difference in IP-10 (p = 0.029*) and medium differences in IL-1RA44Cytokine abbreviations: bFGF; Basic Fibroblast Growth Factor, G-CSF; Granulocyte colony stimulating factor, GM-CSF; Granulocyte-Macrophage Colony-Stimulating Factor, IFN; interferon, IL; Interleukin, IP; Interferon-gamma Inducible Protein, MCP; Monocyte Chemoattractant Protein, MIP; Macrophage Inflammatory Protein, PGDF-BB; Platelet Derived Growth Factor Subunit B, RA; Receptor antagonist, TNF; Tumor Necrosis Factor, VEGF; Vascular Endothelial Growth Factor (p = 0.030*) and IL-12 (p = 0.034*). One cytokine level was significantly higher in the PVD group: a medium difference for IL-6 (p = 0.037*). Due to the lack of consistency in elevation of inflammatory profiles, it is not enough to support persistent inflammation as the etiology behind PVD. However, these findings may indicate there is a possible immune response deficiency in some patients who have PVD. The resemblance of cytokine profile in our study to cytokine profile of people with chronic yeast infection further support this proposed mechanism behind PVD. Future studies involving history and testing for yeast infection are necessary to explore this possibility further.

Lung-brain crosstalk: Behavioral disorders and neuroinflammation in septic survivor mice

Although studies have suggested an association between lung infections and increased risk of neuronal disorders (e.g., dementia, cognitive impairment, and depressive and anxious behaviors), its mechanisms remain unclear. Thus, an experimental mice model of pulmonary sepsis was developed to investigate the relationship between lung and brain inflammation. Male Swiss mice were randomly assigned to either pneumosepsis or control groups. Pneumosepsis was induced by intratracheal instillation of Klebsiella pneumoniae, while the control group received a buffer solution. The model's validation included assessing systemic markers, as well as tissue vascular permeability. Depression- and anxiety-like behaviors and cognitive function were assessed for 30 days in sepsis survivor mice, inflammatory profiles, including cytokine levels (lungs, hippocampus, and prefrontal cortex) and microglial activation (hippocampus), were examined. Pulmonary sepsis damaged distal organs, caused peripheral inflammation, and increased vascular permeability in the lung and brain, impairing the blood-brain barrier and resulting in bacterial dissemination. After sepsis induction, we observed an increase in myeloperoxidase activity in the lungs (up to seven days) and prefrontal cortex (up to 24 h), proinflammatory cytokines in the hippocampus and prefrontal cortex, and percentage of areas with cells positive for ionized calcium-binding adaptor molecule 1 (IBA-1) in the hippocampus. Also, depression- and anxiety-like behaviors and changes in short-term memory were observed even 30 days after sepsis induction, suggesting a crosstalk between inflammatory responses of lungs and brain.

Abstract Or114: Inhibiting IL-1 Signaling to Cardiac Fibroblasts Protects Against Acute Viral Myocarditis

Background: Understanding what factors perpetuate cardiac inflammation in patients with unremitting inflammatory dilated cardiomyopathy (iDCM) is critical for developing curative therapies. We have previously demonstrated that inflammatory fibroblasts (IFs), a subset of cardiac fibroblasts (CFs) that promote inflammation, depend on IL-17A signaling to drive iDCM progression in experimental autoimmune myocarditis. Here, we demonstrate that IL-1 signaling more potently activates IFs than IL-17A. IL-1 signaling has been implicated in the pathogenesis of viral myocarditis, the most common etiology of myocarditis, though the mechanism is unclear. Hypothesis: We hypothesize that IL-1 signaling to CFs induces their differentiation into IFs, which drive pathogenic inflammation during viral myocarditis. Methods: Primary murine CF cultures were used to characterize IF activation by various cytokines. Next, we both performed qPCR on sorted CFs and used a CCL2-mCherry reporter mouse line to phenotype IF activation during Coxsackievirus B3 (CVB3) myocarditis. Finally, in-vivo fibroblast-specific IL-1 signaling was genetically ablated using PDGFRα cre IL1r1 fl/fl mice. We infected PDGFRα cre and PDGFRα cre IL1r1 fl/fl mice with CVB3 and assessed myocarditis severity during the peak of inflammation using histological scoring and flow cytometry. Results: Innate, Th1, Th2, and Th17 related cytokines such as IL-1β, IFNγ, IL-13, and IL-17A induced unique IF gene expression signatures. IL-1β most potently activated IFs with a pro-myeloid cytokine inflammatory profile. During CVB3 myocarditis, IF activation peaked on day 3 post infection and was sustained until day 10. Ablating IL-1 signaling to CFs reduced the magnitude of cardiac inflammation by 45% ± 14% (p=0.002) during the peak of CVB3 myocarditis with a reduction in monocyte, CD4+ T cells, CD8+ T cells, and NK cell recruitment. Gene expression analysis of sorted CFs from mutant and control mice revealed reduced expression of pro-myeloid chemokines such as CXCL1 and CCL2 on day 3 of CVB3 myocarditis. Conclusions: Cardiac fibroblasts exhibit remarkable plasticity allowing them to respond to a changing micro-environment. Blocking IL-1 signaling to IFs during CVB3 myocarditis inhibited production of pro-inflammatory chemokines resulting in attenuation of myocardial inflammation. Therefore, early IF activity acts as a rheostat to modulate the magnitude of cardiac inflammation during myocarditis.

Association of blood inflammatory phenotypes and asthma burden in children with moderate-to-severe asthma

BackgroundUnderlying immunological mechanisms in children with moderate-to-severe asthma are complex and unclear. We aimed to investigate the association between blood inflammatory parameters and asthma burden in children with moderate-to-severe asthma.MethodsBlood inflammatory parameters (eosinophil(E) and neutrophil(N) counts and inflammatory mediators using multiplex immunoassay technology) were measured in children (6–17 years) with moderate-to-severe asthma from SysPharmPediA cohort across four European countries. Based upon low(L)/high(H) blood(B) eosinophil (LBE/HBE: &lt;/≥0.3×109/L, respectively) and neutrophil counts (LBN/HBN: &lt;/≥4×109/L, respectively), mixed(HBE-HBN), eosinophilic(HBE-LBN), neutrophilic(LBE-HBN), and paucigranulocytic(LBE-LBN) phenotypes were defined. Inflammatory mediator profiles and burden of disease (asthma control status, exacerbations and school days missed in the past year) were compared between phenotypes using adjusted logistic regression models.ResultsAmong 126 included children (41% girls and mean(sd) age of 11.94(2.76)), 22%, 44%, 11%, and 23% were classified as mixed, eosinophilic, neutrophilic, and paucigranulocytic phenotypes respectively. Neutrophilic children had lowest lung function (FEV1%predicted pre-salbutamol) compared to other groups. Children with mixed asthma were most often uncontrolled and had highest asthma-related school absence in the past year. Interleukin-6(IL-6) and matrix metalloproteinase-9(MMP-9) levels were significantly higher in patients with mixed or neutrophilic asthma, while tissue inhibitor of metalloproteinase-2(TIMP-2) was lower in patients with neutrophilic asthma compared to eosinophilic or paucigranulocytic asthma. Interleukin-5(IL-5) was increased in eosinophilic group compared to neutrophilic and paucigranulocytic groups, irrespective of the chosen cut-off for eosinophilia.ConclusionDifferences in asthma burden-related clinical expression and distinct blood inflammatory mediator profiles were found between phenotypes, highlighting implications for optimizing personalized treatment and management strategies in children with moderate-to-severe asthma.

Pro-inflammatory activity of Cutibacterium acnes phylotype IA1 and extracellular vesicles: An invitro study.

Acne is a chronic inflammatory skin condition that involves Cutibacterium acnes (C. acnes), which is classified into six main phylotypes (IA1, IA2, IB, IC, II and III). Acne development is associated with loss of C. acnes phylotype diversity, characterised by overgrowth of phylotype IA1 relative to other phylotypes. It was also shown that purified extracellular vesicles (EVs) secreted by C. acnes can induce an acne-like inflammatory response in skin models. We aimed to determine if the inflammatory profile of EVs secreted by C. acnes phylotype IA1 from an inflammatory acne lesion was different from C. acnes phylotype IA1 from normal skin, thus playing a direct role in the severity of inflammation. EVs were produced invitro after culture of two clinical strains of C. acnes phylotype IA1, T5 from normal human skin and A47 from an inflammatory acne lesion, and then incubated with either human immortalised keratinocytes, HaCaT cells, or skin explants obtained from abdominoplasty. Subsequently, quantitative PCR (qPCR) was performed for human β-defensin 2 (hBD2), cathelicidin (LL-37), interleukin (IL)-1β, IL-6, IL-8, IL-17α and IL-36γ, and ELISA for IL-6, IL-8 and IL-17α. We found that EVs produced invitro by C. acnes derived from inflammatory acne lesions significantly increased the pro-inflammatory cytokines and anti-microbial peptides at both transcriptional and protein levels compared with EVs derived from normal human skin. We show for the first time that C. acnes EVs from inflammatory acne play a crucial role in acne-associated inflammation invitro and that C. acnes phylotype IA1 collected from inflammatory acne lesion and normal skin produce different EVs and inflammatory profiles invitro.

Metabolic, Mitochondrial, and Inflammatory Effects of Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate in Asymptomatic Antiretroviral-Naïve People with HIV.

This study aimed to comprehensively assess the metabolic, mitochondrial, and inflammatory effects of first-line efavirenz, emtricitabine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) single-tablet regimen (STR) relative to untreated asymptomatic HIV infection. To this end, we analyzed 29 people with HIV (PWH) treated for at least one year with this regimen vs. 33 antiretroviral-naïve PWH. Excellent therapeutic activity was accompanied by significant alterations in metabolic parameters. The treatment group showed increased plasmatic levels of glucose, total cholesterol and its fractions (LDL and HDL), triglycerides, and hepatic enzymes (GGT, ALP); conversely, bilirubin levels (total and indirect fraction) decreased in the treated cohort. Mitochondrial performance was preserved overall and treatment administration even promoted the recovery of mitochondrial DNA (mtDNA) content depleted by the virus, although this was not accompanied by the recovery in some of their encoded proteins (since cytochrome c oxidase II was significantly decreased). Inflammatory profile (TNFα, IL-6), ameliorated after treatment in accordance with viral reduction and the recovery of TNFα levels correlated to mtDNA cell restoration. Thus, although this regimen causes subclinical metabolic alterations, its antiviral and anti-inflammatory properties may be associated with partial improvement in mitochondrial function.

Novel Susceptibility Genes and Biomarkers for Obstructive Sleep Apnea: Insights from Genetic and Inflammatory Proteins.

Numerous observational studies link obstructive sleep apnea (OSA) to inflammatory proteins, yet the directionality of these associations remains ambiguous. Therefore, we aimed to clarify the potential associations of gene-predicted inflammatory proteins with OSA. Based on genome-wide association study data, we applied Mendelian randomization (MR) to explore potential connections between circulating inflammatory proteins and OSA, primarily using the inverse variance weighting method for robustness. Cochran's Q test, MR‒Egger intercept test, MR-PRESSO, and leave-one-out method were used to perform sensitivity tests for pleiotropy and heterogeneity. Replication analyses and meta-analyses were performed using other independent data. Steiger tests and multivariate MR assessed the independent effects of exposure factors, and the functional mapping and annotation (FUMA) platform was used to identify key genes to enhance the understanding of genetics. Our investigation revealed 21 circulating inflammatory proteins significantly associated with OSA-related phenotypes. Notably, IL-10RA, IL-18R1, TNFSF14, CCL23, ADA, and SLAMF1 had significant effects on multiple phenotypes. After FDR correction, IL-18R1, SLAMF1, IL-10RA, and IL-17C were identified as important candidates for OSA, and multivariate MR analysis strengthened the independent heritability of 20 inflammatory factors. The FUMA platform revealed seven overlapping genes: ROBO1, PRIM1, NACA, SHBG, HSD17B6, RBMS2, and WWOX. All reverse MR analyses and sensitivity analyses confirmed the robustness of these associations. Our results underscore crucial associations between inflammatory proteins and OSA pathogenesis, revealing new correlates and susceptibility genes. These findings advance biomarker identification for OSA risk and highlight the importance of genetic and inflammatory profiles in OSA management.