IL-1 Receptor Agonist Research Articles

Pro-inflammatory cytokines and antioxidative enzymes as salivary biomarkers of dentofacial infections in children.

Dentofacial infection resulting from untreated dental caries or periodontal disease is a serious disease that can spread to deeper tissues of the face and neck. The present study aimed to analyze the salivary cytokine profile and oxidative stress parameters as potential biomarkers of acute odontogenic infections in children. The prospective study group (DI) consisted of 28 children aged 3-17 years with acute dentofacial infections, and the control group (CG) comprised 52 children aged 4-17 years with uncomplicated dental caries. The cytokine profile was analyzed using the Bio-Plex Pro™ Human Cytokine 27-plex kit. In addition, oxidative stress parameters, such as catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), manganese SOD (Mn-SOD), copper-zinc SOD (CuZn-SOD), total antioxidant capacity (TAC), total oxidant status (TOS), and malondialdehyde (MDA), in the saliva of children in both groups were compared. The levels of interleukin 6 (IL-6), macrophage inflammatory protein 1 alpha (MIP-1α) and tumor necrosis factor alpha (TNF-α) were significantly increased in children with dentofacial infections as compared to CG. In contrast, the levels of other pro-inflammatory cytokines, such as IL-1β, IL-1 receptor agonist (IL-Ra), IL-8, monocyte chemoattractant protein 1 (MCP-1), and MIP-1β, did not show statistically significant differences between the 2 groups. Among the measured oxidative stress and antioxidative parameters, only CAT and GR were elevated in children with dentofacial infections as compared to controls. IL-6, MIP-1α, TNF-α, CAT, and GR can serve as selective biomarkers of oral cavity inflammation in children. These biomarkers can be useful in identifying and monitoring the progress and treatment of bacterial infections resulting in dentofacial inflammation.

Sustained IL-6 and sTNF-αR1 levels after hip fracture predict 5-year mortality: A prospective cohort study from the Baltimore Hip Studies.

Persistent inflammation is associated with adverse health outcomes, but its impact on mortality has not been investigated previously among hip fracture patients. This article aims to investigate the influence of changes in levels of cytokines in the 2 months after a hip fracture repair on 5-year mortality. This is a prospective cohort study from the Baltimore Hip Studies (BHS) with 191 community-dwelling older men and women (≥65 years) who had recently undergone surgical repair of an acute hip fracture, with recruitment from May 2006 to June 2011. Plasma interleukin-6 (IL-6), soluble tumor necrosis factor alpha receptor1 (sTNFα-R1), and interleukin-1 receptor agonist (IL-1RA) were obtained within 22 days of admission and at 2 months. All-cause mortality over 5 years was determined. Logistic regression analysis tested the associations between the cytokines' trajectories and mortality over 5 years, adjusted for covariates (age, sex, education, body mass index, lower extremity physical activities of daily living, and Charlson comorbidity index). High levels of IL-6 and sTNFα-R1 at baseline with small or no decline at 2 months were associated with higher odds of 5-year mortality compared with those with lower levels at baseline and greater decline at 2 months after adjustment for age, and other potential confounders (OR = 4.71, p = 0.01 for IL-6; OR = 15.03, p = 0.002 for sTNFα-R1). Similar results that failed to reach significance were found for IL-1RA (OR = 2.40, p = 0.18). Those with higher levels of cytokines at baseline with greater decline did not have significantly greater mortality than the reference group, those with lower levels at baseline and greater decline. Persistent elevation of plasma IL-6 and sTNFα-R1 levels within the first 2 months after hospital admission in patients with hip fracture is associated with higher 5-year mortality. These patients may benefit from enhanced care and earlier intensive interventions to reduce the risk of death.

Cytokine profiling in 128 patients with transient abnormal myelopoiesis: a report from the JPLSG TAM-10 trial

AbstractTransient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in ∼20% of cases. Therefore, new biomarkers are needed to predict early death and determine therapeutic interventions. This study aimed to determine the association between clinical characteristics and cytokine levels in patients with TAM. A total of 128 patients with DS with TAM enrolled in the TAM-10 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group were included in this study. Five cytokine levels (interleukin-1b [IL-1b], IL-1 receptor agonist, IL-6, IL-8, and IL-13) were significantly higher in patients with early death than in those with nonearly death. Cumulative incidence rates (CIRs) of early death were significantly associated with high levels of the 5 cytokines. Based on unsupervised consensus clustering, patients were classified into 3 cytokine groups: hot-1 (n = 37), hot-2 (n = 42), and cold (n = 49). The CIR of early death was significantly different between the cytokine groups (hot-1/2, n = 79; cold, n = 49; hot-1/2 CIR, 16.5% [95% confidence interval (CI), 7.9-24.2]; cold CIR, 2.0% [95% CI, 0.0-5.9]; P = .013). Furthermore, cytokine groups (hot-1/2 vs cold) were independent poor prognostic factors in the multivariable analysis for early death (hazard ratio, 15.53; 95% CI, 1.434-168.3; P = .024). These results provide valuable information that cytokine level measurement was useful in predicting early death in patients with TAM and might help to determine the need for therapeutic interventions. This trial was registered at UMIN Clinical Trials Registry as #UMIN000005418.

Pro- and Anti-Inflammatory Responses Following Active and Passive Ascent to 3600 m

Lowlanders who develop acute mountain sickness (AMS) following rapid ascent to high altitude (HA) demonstrate increased levels of both pro-inflammatory (tumor necrosis factor α (TNFα), Interleukin (IL)- 1β, IL-6, IL-8, and IL-17α) and anti-inflammatory biomarkers (IL-10 and IL-1 receptor agonist; IL-1ra). Whether ascending by self-locomotion (i.e., active ascent) modulates these pro- and anti-inflammatory cytokine responses at HA is unknown. We hypothesized a greater pro-inflammatory response in the AMS-susceptible group following active ascent. To test this hypothesis, 78 healthy Soldiers (mean±SD; age, 26±5yr) were tested at baseline residence (BLR), transported to Taos, NM (2845m), then hiked (n=39) or were driven (n=39) to HA (3600m), and stayed for 4 days. AMS-Cerebral factor score (AMS-C) was assessed using the Environmental Symptoms Questionnaire (ESQ) at HA twice on day 1 (HA1). If AMS-C was ≥0.7 at either assessment, individuals were categorized as AMS-susceptible (AMS+; n=24); others were AMS-resistant (AMS−; n=54). Fasting blood samples were taken at 06:00 at BLR, HA2, HA3 and HA4 and analyzed to determine cytokine (TNFα, IL-1β, IL-6, IL-8, IL-10, IL-17α, and IL-1ra) responses following the initial hypoxic insult. Blood values (pg/mL) were log-transformed and adjusted for plasma volume changes from BLR to HA. The active group expended a greater ( p<0.05) amount of energy (745±435 kcal) than the passive group (55±10 kcal) during ascent. There were no differences in biomarkers between ascent groups, so data were combined. In the AMS-susceptible group, IL-17α increased ( p<0.05) from BLR to HA2 (63.3±8.8 to 73.1±8.8, p=0.002) and remained increased at HA3 (70.1±8.8) and HA4 (73.1±8.8). In the AMS-resistant group, IL-17α did not change from BLR to any of the days at HA. Independent of AMS susceptibility, the anti-inflammatory marker IL-1ra increased from BLR to HA2 (63.5±11.4 to 89.9±11.4, p=0.013) and then fell back down to BLR values on HA3 (70.4±11.4, p=0.560) and HA4 (71.8±11.4, p=0.537). When all days were combined, TNFα (+15%, p=0.036), IL-6 (+50%, p=0.042), and IL-10 (+36%, p=0.040) were increased in the AMS-susceptible compared to the AMS-resistant group. IL-1β and IL-8 did not change ( p>0.05) from BLR to any time point at HA in either group. In conclusion, both a robust pro- (TNFα, IL-6, IL-17α) and anti-inflammatory (IL-10) response occurred at HA in those susceptible to AMS most likely due to inflammation following the initial hypoxic insult followed quickly by an anti-inflammatory response. However, ascent strategy on HA1 had no impact on pro- or anti-inflammatory cytokines on days 2-4 at HA. Authors’ views not offcial U.S. Army or DoD policy. Funding: USAMRDC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

NEURODEGENERATION BIOMARKERS HELP EXPLAIN ASSOCIATION BETWEEN INFLAMMATION AND COGNITIVE DYSFUNCTION

Abstract There is past evidence that immune aging (or immunosenescence) and high systemic inflammation are associated with cognitive dysfunction and ADRD. However, it is unknown whether these immune-related aging processes are associated with neurodegeneration, tauopathy, amyloid accumulation, and/or vascular issues in the brain. To address this gap, we utilized a set of recently assayed highly innovative markers of neurodegeneration, biomarkers of inflammation, and proportions of naïve lymphocytes (indicative of less immune aging), and cognitive dysfunction (errors on the Telephone Interview for Cognitive Status) in the Health and Retirement Study, a nationally representative sample of US adults over age 50 (N = 3985). Using structural equation modeling (SEM), we estimated latent factors representing neurodegeneration (neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphotau 181 (pTau181)), inflammation (c-reactive protein, IL10, IL1 receptor agonist, IL6, TNF receptor 1, albumin, and percentage of neutrophils), and immune aging (percentages of naïve CD8+ and CD4+ T cells). Results indicate inflammation is associated with neurodegenerative biomarkers (β = .31, p < .001) and with cognitive dysfunction (β = .08, p < .001) after controlling for age, race, gender, education, BMI, smoking, drinking, and immunosenescence. Neurodegenerative biomarkers mediated about half of the association between inflammation and cognitive dysfunction. It appears that greater systemic inflammation may be associated with brain damage and tauopathy. Interventions focused on reducing systemic inflammation may be successful in reducing neurodegeneration and cognitive dysfunction in older adults.

Poster 121: Association Between MRI Findings in ACL Injury and Subacute Synovial Fluid Inflammatory Biomarker Levels at the Time Of Surgery

Objectives: To Investigate the association between MRI findings following anterior cruciate ligament (ACL) injury and synovial fluid biomarker profile at the time of surgery Methods: Patients undergoing surgery for ACL injury from October 2011 to December 2021 were included in a database of subjects who had synovial fluid samples collected at the time of surgery. From this cohort, 82 subjects with acute ACL injury were retrospectively selected who met the following inclusion criteria: no history of prior knee trauma to suggest chronic ACL injury, history of acute non- contact knee injury, MRI examination of the knee performed within 3 weeks of knee injury, subsequent knee surgery performed between 4 and 12 weeks of knee injury, and no additional ligament tear requiring surgical treatment. All subjects underwent a preoperative MRI examination of the knee using multi-planar, multi-contrast fast spin-echo sequences. Synovial fluid was aspirated from the operative knee prior to surgical incision. Concentrations of inflammatory biomarkers including regulation on activation normal T cell expressed and secreted (RANTES), interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), tissue inhibitor matrix metalloproteinase 1 (TIMP1), interleukin 1 receptor agonist (IL1-RA) and matrix metalloproteinase 3 (MMP-3) were measured. The MRI examinations of all subjects were reviewed by a fellowship trained musculoskeletal radiologist to assess the presence and severity of various MRI features of acute and chronic knee injury using the validated Anterior Cruciate Ligament Osteoarthritis Score (ACLOAS) system. Nonparametric Wilcoxon tests and Fisher’s exact test were used to compare demographic factors, MRI findings, clinical symptoms, and synovial fluid inflammatory biomarkers between clusters. K-means cluster analysis was used to identify 2 distinct clusters of subjects with acute ACL injury based on biomarkers concentrations in synovial fluid. Results: The mean age of the cohort was 31.6 ± 8 years, average body mass index (BMI) was 25.5 ± 4.4 kg/m2. There 42.7% (n=35) of the cohort was female and 85.4% (n=70) were non-smokers. Two distinct clusters were identified: cluster 1 included 45 subjects and was marked by older subjects (33.2 ± 9.1 years, p=.038) with lower levels of all inflammatory synovial fluid biomarkers. Cluster 2 included 37 subjects and was marked by younger patients (29.7 ± 6.1 years, p=.038) with a more pro-inflammatory synovial fluid biomarker profile, higher ACLOAS Hoffa’s synovitis score (p=.001), and a higher incidence of subchondral bone fractures (54%, p=.002). There were no differences between clusters in time from injury to surgery (p=), BMI (p=.141), or ACLOAS meniscus (p=.086), cartilage (p=.730), or effusion scores (p=.202) Conclusions: Given the variable outcomes seen following ACL reconstruction (ACLR) surgery, a better understanding of the pathophysiology following ACL injury is needed. This study found distinct cluster of patients who exhibited a higher inflammatory reaction at the time of surgery as well as more severe findings on preoperative MRI. These findings could be used to identified clinical parameters associated with more inflammation at the time of surgery and their effect on clinical outcomes of ACLR.

Circulating markers of intestinal barrier injury and inflammation following exertion in hypobaric hypoxia

ABSTRACT Hypoxia induced intestinal barrier injury, microbial translocation, and local/systemic inflammation may contribute to high-altitude associated gastrointestinal complications or symptoms of acute mountain sickness (AMS). Therefore, we tested the hypothesis that six-hours of hypobaric hypoxia increases circulating markers of intestinal barrier injury and inflammation. A secondary aim was to determine if the changes in these markers were different between those with and without AMS. Thirteen participants were exposed to six hours of hypobaric hypoxia, simulating an altitude of 4572 m. Participants completed two 30-minute bouts of exercise during the early hours of hypoxic exposure to mimic typical activity required by those at high altitude. Pre- and post-exposure blood samples were assessed for circulating markers of intestinal barrier injury and inflammation. Data below are presented as mean ± standard deviation or median [interquartile range]. Intestinal fatty acid binding protein (Δ251 [103-410] pg•mL−1; p = 0.002, d = 0.32), lipopolysaccharide binding protein (Δ2 ± 2.4 μg•mL−1; p = 0.011; d = 0.48), tumor necrosis factor-α (Δ10.2 [3-42.2] pg•mL−1; p = 0.005; d = 0.25), interleukin-1β (Δ1.5 [0-6.7] pg•mL−1 p = 0.042; d = 0.18), and interleukin-1 receptor agonist (Δ3.4 [0.4-5.2] pg•mL−1 p = 0.002; d = 0.23) increased from pre- to post-hypoxia. Six of the 13 participants developed AMS; however, the pre- to post-hypoxia changes for each marker were not different between those with and without AMS (p > 0.05 for all indices). These data provide evidence that high altitude exposures can lead to intestinal barrier injury, which may be an important consideration for mountaineers, military personnel, wildland firefighters, and athletes who travel to high altitudes to perform physical work or exercise.

Time course of serum cytokine level changes within 72 h after onset in children with acute encephalopathy and febrile seizures

BackgroundCytokine levels have been measured in acute encephalopathy (AE) to determine its pathology or as a diagnostic biomarker to distinguish it from febrile seizures (FS); however, the dynamics of cytokine level changes have not yet been fully captured in these two neurological manifestations. Thus, we aimed to explore the time course of serum cytokine level changes within 72 h after onset in AE and FS.MethodsWe retrospectively measured cytokine level in residual serum samples at multiple timepoints in seven children whose final diagnoses were AE or FS.ResultsThe levels of 13 cytokines appeared to increase immediately after onset and peaked within 12–24 h after onset: interleukin (IL)-1β, IL-4 IL-5, IL-6, IL-8, IL-10, IL-17, eotaxin, fibroblast growth factor, granulocyte colony-stimulating factor, interferon gamma, interferon-inducible protein-10, and macrophage chemoattractant protein-1. There were no dynamic changes in the levels of three cytokines (IL-1 receptor agonist, macrophage inflammatory protein-1α, and platelet-derived growth factor-bb) 72 h after onset. Levels of some cytokines decreased to around control levels within 48 h after onset: IL-1β, IL-4, IL-5, IL-17, fibroblast growth factor, and interferon gamma. The levels of most cytokines appeared to be higher in AE, especially in hemorrhagic shock encephalopathy syndrome, than in FS.ConclusionsCytokine levels in both AE and FS change dynamically, such as the levels of several cytokines increased within a few hours after onset and decreased at 12–24 h after onset. Therefore, it will be desirable to make clinical decisions regarding the administration of anti-inflammatory therapy in 24 h after onset in AE.

Inhibition of Both IRAK1 and IRAK4 Is Required for Complete Suppression of NF-Kb Signaling across Multiple Receptor-Mediated Pathways in MDS and AML

There is increasing interest in the role of the IRAK kinases as targets in the treatment of MDS and AML (reviewed in J Bennett and DT Starczynowski, Curr Opin Hematol 2022). IRAK1 and IRAK4 lie downstream of multiple receptors that stimulate the canonical NF-κB signaling pathway upstream of TRAF6 via the myddosome complex. While TRAF6 is necessary to preserve the tonic NF-κB signaling that is required for hematopoietic stem cell (HSC) homeostasis (J Fang et. al. Cell Reports 2018), overactivity of the NF-κB signaling pathway has been implicated in both MDS and AML (reviewed in MCJ Bosman et. al., Crit Rev Oncol/Hematol 2016; JJ Trowbridge and DT Starczynowski, J Exp Med 2021). The requirement for both IRAK1 and IRAK4 in this pathway has been explored using both genetic and pharmacologic technologies. The use of genetic loss-of-function approaches revealed that deletion and/or inhibition of IRAK4 results in a compensatory increase in IRAK1 protein and activation (data unpublished), suggesting that high potency antagonism of both kinases will be required for optimal inhibition of NF-κB-mediated transcriptional responses in disease-propagating MDS and AML cells. In this report, we use a pharmacological approach in which a series of IRAK inhibitors of varying relative potency at IRAK1:IRAK4 were examined for both inhibition of NF-κB activation in AML cells and inhibition of leukemic progenitor cell function in vitro. We find that potency and efficacy for antagonism at NF-κB requires effective inhibition of both IRAK1 and IRAK4. We also find that the relative potency of NF-κB inhibition correlates with suppression of leukemic progenitor cell function in vitro, providing pharmacological validation that inhibition of both IRAK1 and IRAK4 are necessary for optimal inhibition of NF-κB and effect on leukemia progenitor cell function. We utilized an NF-κB reporter system expressed in human AML cells (THP1) to measure NF-κB dependent activation in response to a variety of IRAK4, IRAK1, or IRAK1/4 antagonists. The cells are highly responsive to both TLR agonists as well as to IL-1b, which allows for measurement of IRAK-mediated antagonism of multiple receptor-mediated pathways. Using the IRAK4-selective antagonists PF-06650833 and BAY 1834845 we find that both compounds fully suppress signaling through TLR2 (IC50vs. Pam3CSK4 = 7.2 and 150 nM, respectively). The IRAK4 antagonists inhibit signaling through the IL-1R with similar relative potency (IC50vs. IL-1b = 5.7 and 81 nM), but do not fully suppress signaling through this receptor (Span = 75% and 59%, respectively). Interestingly, the IRAK1 selective covalent inhibitor JH-X-119-01 does not inhibit signaling against either the TLR or the IL-1 receptor agonist. Together these data imply that neither IRAK4 nor IRAK1 inhibition alone is sufficient to fully inhibit NF-κB-mediated signaling through multiple receptor mediated pathways. For this reason, we then examined the activity of a series of IRAK4/IRAK1 inhibitors in AML cells. This allowed us to study the effect of adding in additional inhibitory activity at IRAK1 on the background of high potency IRAK4 inhibitors. Using two reference compounds with varying IRAK1:IRAK4 potency, we then compared the relative ability to inhibit TLR-agonist or IL-1b-agonist stimulated NF-κB activity in AML. KME-2780 has an IRAK1:IRAK4 potency ratio of 36 whereas KME-3859 has an IRAK1:IRAK4 potency ratio of 100. Unlike what we observed with the IRAK4-selective antagonists, both compounds can completely suppress NF-κB signaling through IL-1b, with relative potencies apparently determined by their activity at IRAK1: (IC50vs. Pam3CSK4 = 6.3 and 73.8 nM for KME- 2780 and KME-3859, respectively); (IC50vs. IL-1b = 9.3 and 227 nM for KME- 2780 and KME-3859, respectively). Finally, we examined the correlation between potency in the biochemical kinase assay at IRAK1 or IRAK4, activity in the NF-κB reporter assay, and leukemic progenitor cell activity in the colony forming assay for a series of KME compounds in AML and MDS cells. We find a correlation between kinase activity for both IRAK1 and IRAK4 and NF-κB activity that extends to the leukemia colony forming assays. This suggests that NF-κB signaling contributes to leukemia progenitor cell function and that optimal inhibition requires potent antagonism of both IRAK1 and IRAK4 in the setting of MDS and AML.

Axl-RTK Inhibition Modulates Monocyte Immune Response to Enhance the Anti-Tumor Effects of CD19 Redirected Chimeric Antigen Receptor T Cells in Preclinical Models

Axl-RTK Inhibition Modulates Monocyte Immune Response to Enhance the Anti-Tumor Effects of CD19 Redirected Chimeric Antigen Receptor T Cells in Preclinical Models

Baseline interleukin1beta expression in peripheral blood monocytes predicts the extent of weight loss and nonalcoholic fatty liver improvement in obese subjects with prediabetes or type 2 diabetes

Abstract Background Non-alcoholic fatty liver disease (NAFLD) represents a hallmark of metabolic syndrome. Interleukin-1β (IL-1β), a well-studied cytokine involved in obesity-related systemic inflammation as well as in the pathogenesis of type 2 diabetes (T2D), promotes hepatic steatosis by stimulating triglycerides and cholesterol accumulation in primary liver hepatocytes and lipid droplets formation. The most compelling evidence for a major role for IL-1β in metabolic imbalance and inflammation comes from the recent Canakinumab Anti-inflammatory Thrombosis Outcome (CANTOs)trial, where inhibition of IL-1β pathway was associated with a reduction of cardiovascular events in high-risk patients. Purpose The present study was designed to determine: i)whether an equal degree of weight loss by liraglutide or lifestyle changes has a different impact on NAFLD extent and IL-1β expression in peripheral blood mononuclear cells from obese subjects with prediabetes or early T2D; ii)whether baseline IL-1β levels may predict the extent of weight loss and related metabolic changes. Methods Thirty-two metformin-treated obese subjects with prediabetes [impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) or both (n=16)] or newly diagnosed T2D (n=16), were randomized to the glucagon-like peptide receptor agonist (GLP-RA) liraglutide (1.8 mg/d) or lifestyle counselling until achieving a modest and comparable weight loss (−7% of initial body weight). Visceral (VAT) and adipose tissue distribution were assessed by magnetic resonance. Gene expression of IL-1β in peripheral blood mononuclear cells was assessed by real time PCR. Results At baseline, IL-1β positively correlated to body mass index (BMI) (rho=0.421, p=0.016), fasting plasma glucose (rho=0.415, p=0.018), HbA1c (rho=0.349, p=0.050), VAT (rho=0.388, p=0.028), NAFLD (rho=0.454, p=0.009), platelet count (rho=0.510, p=0.003), chemerin (rho=0.455, p=0.009) and interleukin-1 receptor agonist (IL1-RA) (rho=0.519, p=0.002). After achievement of the weight loss target in the two groups, a comparable reduction of IL-1 β (p<0.001 lifestyle changes; p=0.029 liraglutide treatment) was observed in both arms, in parallel with a comparable improvement in glycaemic control, C-reactive protein (CRP),BMI and NAFLD. Furthermore, basal levels of IL-1β correlated directly with delta BMI (p=0.015) and delta NAFLD (p=0.002) (Figure 1). Conclusion In obese patients with initial impairment of glucose metabolism, IL-β-driven inflammation correlates with glycaemic control, adipose tissue distribution and platelet count. Successful weight loss, achieved with either lifestyle changes or an incretin-based therapy, is associated with a significant reduction of both IL-1β levels and NAFLD degree. Of interest, basal levels of IL-1β predicts the extent of weight loss and NAFLD improvement, regardless of the intervention. Our results may set the stage for ad-hoc studies investigating the usefulness of baseline IL-1β a levels as a drug-response biomarker. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by a grant from the Italian Ministry of University and Research (PRIN no. 2010JS3PMZ to F.S.).

The role of interleukin-33 in patients with mild cognitive impairment and Alzheimer\u2019s disease

BackgroundThe neuroprotective role of interleukin (IL)-33 is supported by numerous preclinical studies, but it remains uninvestigated in clinical studies of Alzheimer’s disease (AD). We aimed to examine the association between human blood levels of IL-33 and cognitive preservation in amnestic mild cognitive impairment (aMCI) and AD.MethodsA total of 100 participants (26 controls, 35 aMCI patients, and 39 AD patients) completed two Mini-Mental State Examinations (MMSEs) over a 1-year interval. In all 100 participants at the second MMSE, we examined the plasma levels of IL-33, IL-β, IL-1 receptor agonist (IL-1RA), beta amyloid (Aβ), and tau and apolipoprotein E (ApoE) genotyping; we also performed Hopkins Verbal Learning Test, Trail Making Test, forward and backward digit span, and Clinical Dementia Rating.ResultsIL-33 expression showed a positive trend among controls (1/26 = 3.8%), aMCI (9/35 = 25.7%), and AD (17/39 = 43.6%) (trend analysis: P < 0.001). Patients expressing IL-33 preserved their cognitive function compared with IL-33 non-expressing patients (1-year ΔMMSE, 0.16 ± 1.6 vs − 1.5 ± 2.6; P = 0.006). The cognitive preservation was not associated with the lower levels of Aβ, tau, and ApoE ε4, while higher levels of ApoE ε4 and phosphorylated tau were indeed associated with cognitive decline. The aMCI patients with AD conversion during study period had higher proportion of IL-33(−) than non-AD converters (90.9% vs 53.3%, P = 0.04).ConclusionsIL-33 or its associated signaling pathways may represent a new treatment paradigm for aMCI and AD.

Author response: Acute elevation of serum inflammatory markers predicts symptom recovery after concussion.

We thank Dr. Sethi for the comment and inquiry. In this sample,1 no concussed athletes reported loss of consciousness and only 2 athletes reported posttraumatic amnesia. Thus, we were unable to appropriately address the potential effects of these injury characteristics on the studied markers. Regarding the normalization of the inflammatory markers relative to symptom resolution, as seen in figure 2,1 the levels of interleukin-1 receptor agonist and interleukin-6 returned to the baseline levels by the 24–48-hour visit, whereas symptom severity scores remained elevated. That is, elevations in these inflammatory markers resolved before the symptoms did and the inflammatory markers only showed a prognostic promise when collected within 6 hours postinjury.

The Role of Interleukin-33 in Patients with Mild Cognitive Impairment and Alzheimer's Disease

Objective: The neuroprotective role of Interleukin (IL)-33 is supported in numerous pre-clinical studies but remains mostly uninvestigated in clinical studies of Alzheimer’s disease (AD). We aimed to examine the association between human blood levels of IL-33 and cognitive preservation in amnestic mild cognitive impairment (aMCI) and AD. Methods: A total of 100 participants (26 controls, 35 aMCI patients, and 39 AD patients) were completed twice Mini Mental State Examination (MMSE) over a 1-year interval. At the second MMSE, the 100 participants examined the plasma levels of IL-33, IL-β, IL-1 receptor agonist (IL-1RA), beta amyloid (Aβ), and tau and apolipoprotein E (ApoE) genotyping, and Hopkins Verbal Learning Test, Trail Making Test, forward and backward digit span, and Clinical Dementia Rating were performed as well. Results: IL-33 expression showed a positive trend among controls (1/26 = 3.8%), aMCI (9/35 = 25.7%), and AD (17/39 = 43.6%) (trend analysis: P < 0.001). The patients expressing IL-33 preserved their cognitive function compared with IL-33 non-expressing patients (1-year ΔMMSE: 0.16 ± 1.6 vs -1.5 ± 2.6; P = 0.006). The cognitive preservation was not associated with the lower levels of Aβ, tau, and AopE e4, while higher levels of AopE e4 and phosphorylated tau were indeed associated with cognitive decline. The aMCI patients with AD conversion during study period had higher proportion of IL-33(-) than non-AD converters (0.9% vs 53.3%, P = 0.04). Conclusions: IL-33 or its associated signaling pathways may represent a new treatment paradigm for aMCI and AD. Funding Statement: Supported by grants from the Ministry of Science and Technology of Taiwan (MOST 106-2314-B-016-007-MY2, MOST 108-2314-B-016-023-), Tri-Service General Hospital (TSGH-C106-068, TSGH-C108-100, TSGH-C108-216), and Beitou Branch, Tri-Service General Hospital (TSGH-BT-108-01). Declaration of Interests: All authors declare that there is no conflict of interest regarding the publication of this article. Ethics Approval Statement: The protocol was approved by the Institutional Review Board for the Protection of Human Subjects at the Tri-Service General Hospital (TSGHIRB 1-107-05-111). Informed consent was obtained from all participants.

Efficacy and Safety of Intense Pulsed Light in Patients With Meibomian Gland Dysfunction-A Randomized, Double-Masked, Sham-Controlled Clinical Trial.

To study the efficacy and safety of intense pulsed light (IPL) in patients with meibomian gland dysfunction (MGD). This prospective randomized double-masked sham-controlled trial included 114 patients with MGD. Patients were randomized into the IPL or sham group. Either the IPL or sham procedure was performed on days 0, 15, and 45. Ocular Surface Disease Index (OSDI), visual analog scale, visual acuity, tear breakup time, meibum quality and expressibility, meibography grade, ocular surface staining, tear film lipid layer thickness, tear osmolarity, Schirmer test, tear interleukin-1 receptor agonist, and interleukin-6 levels were examined on days 0, 15, and 45 and at months 3 and 6. Subgroup analysis according to stage and the patient's compliance to conventional treatment were also analyzed. Any adverse events during the study were recorded. A multilevel mixed-effect linear regression model was used. P value less than 0.05 was considered statistically significant. At 6 months, tear breakup time, meibum quality grades, expressibility grades, and OSDI were better in the IPL group (5.23 ± 2.91 vs. 3.11 ± 0.99 seconds, P < 0.001; 8.74 ± 4.74 vs. 13.19 ± 5.01, P < 0.001; 0.50 ± 0.67 vs. 1.12 ± 0.70, P < 0.001; 24.29 ± 16.92 vs. 32.71 ± 20.07, P < 0.05). OSDI, meibum quality, and expressibility in the IPL group began to improve at day 15 (P < 0.001), whereas the results in the sham group began to improve at day 45 (P < 0001). No adverse event occurred after IPL. IPL is effective and safe for MGD treatment in all stages regardless of compliance.

Longitudinal multi-omics of host\u2013microbe dynamics in prediabetes

Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2D better, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host–microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.

The Chlamydia trachomatis Plasmid and CT135 Virulence Factors Are Not Essential for Genital Tract Infection or Pathology in Female Pig-Tailed Macaques.

ABSTRACTThe Chlamydia trachomatis plasmid and inclusion membrane protein CT135 are virulence factors in the pathogenesis of murine female genital tract infection. To determine if these virulence factors play a similar role in female nonhuman primates, we infected pig-tailed macaques with the same C. trachomatis strains shown to be important in the murine model. Wild-type C. trachomatis and its isogenic mutant strain deficient in both plasmid and CT135 were used to infect macaques. Macaques were given primary and repeated cervicovaginal challenges with the wild-type and mutant strains. The infection rate, infection duration, and antibody response were similar among macaques infected with both strains. Unexpectedly, colposcopy, laparoscopy, and histologic analysis revealed no substantial genital tract pathology following either primary or repeated cervicovaginal challenges. Cytokine analysis of cervicovaginal secretions from both challenged groups revealed low concentrations of interleukin 1β (IL-1β) and elevated levels of the interleukin 1 receptor agonist (IL-1RA). We propose that an imbalance of IL-1β and IL-1RA in macaques is the reason for the mild inflammatory responses observed in infected urogenital tissues. Thus, understanding the pathobiology of chlamydial infection requires a better understanding of host epigenetic and chlamydial genetic factors. Our findings also have implications for understanding the high frequency of asymptomatic infections in humans.

Platelet-Rich Plasma Powder: A New Preparation Method for the Standardization of Growth Factor Concentrations

Background: Platelet-rich plasma (PRP) is widely used in sports medicine. Available PRP preparations differ in white blood cell, platelet, and growth factor concentrations, making standardized research and clinical application challenging. Purpose: To characterize a newly standardized procedure for pooled PRP that provides defined growth factor concentrations. Study Design: Controlled laboratory study. Methods: A standardized growth factor preparation (lyophilized PRP powder) was prepared using 12 pooled platelet concentrates (PCs) derived from different donors via apheresis. Blood samples and commercially available PRP (SmartPrep-2) served as controls (n = 5). Baseline blood counts were analyzed. Additionally, single PCs (n = 5) were produced by standard platelet apheresis. The concentrations of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor AB (PDGF-AB), transforming growth factor β1 (TGF-β1), insulin-like growth factor 1 (IGF-1), interleukin (IL)–1α, IL-1β, and IL-1 receptor agonist (IL-1RA) were analyzed by enzyme-linked immunosorbent assay, and statistical analyses were performed using descriptive statistics, mean differences, 95% CIs, and P values (analysis of variance). Results: All growth factor preparation methods showed elevated concentrations of the growth factors VEGF, bFGF, PDGF-AB, and TGF-β1 compared with those of whole blood. Large interindividual differences were found in VEGF and bFGF concentrations. Respective values (mean ± SD in pg/mL) for whole blood, SmartPrep-2, PC, and PRP powder were as follows: VEGF (574 ± 147, 528 ± 233, 1087 ± 535, and 1722), bFGF (198 ± 164, 410 ± 259, 151 ± 99, and 542), PDGF-AB (2394 ± 451, 17,846 ± 3087, 18,461 ± 4455, and 23,023), and TGF-β1 (14,356 ± 4527, 77,533 ± 13,918, 68,582 ± 7388, and 87,495). IGF-1 was found in SmartPrep-2 (1539 ± 348 pg/mL). For PC (2266 ± 485 pg/mL), IGF-1 was measured at the same levels of whole blood (2317 ± 711 pg/mL) but was not detectable in PRP powder. IL-1α was detectable in whole blood (111 ± 35 pg/mL) and SmartPrep-2 (119 ± 44 pg/mL). Conclusion: Problems with PRP such as absent standardization, lack of consistency among studies, and black box dosage could be solved by using characterized PRP powder made by pooling and lyophilizing multiple PCs. The new PRP powder opens up new possibilities for PRP research as well as for the treatment of patients. Clinical Relevance: The preparation of pooled PRP by means of lyophilization may allow physicians to apply a defined amount of growth factors by using a defined amount of PRP powder. Moreover, PRP powder as a dry substance with no need for centrifugation could become ubiquitously available, thus saving time and staff resources in clinical practice. However, before transferring the results of this basic science study to clinical application, regulatory issues have to be cleared.

Aloin Inhibits Interleukin (IL)-1β-Stimulated IL-8 Production in KB Cells.

Interleukin (IL)-1β, which is elevated in oral diseases including gingivitis, stimulates epithelial cells to produce IL-8 and perpetuate inflammatory responses. This study investigates stimulatory effects of salivary IL-1β in IL-8 production and determines if aloin inhibits IL-1β-stimulated IL-8 production in epithelial cells. Saliva was collected from volunteers to determine IL-1β and IL-8 levels. Samples from volunteers were divided into two groups: those with low and those with high IL-1β levels. KB cells were stimulated with IL-1β or saliva with or without IL-1 receptor agonist or specific mitogen-activated protein kinase (MAPK) inhibitors. IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA). MAPK protein expression involved in IL-1β-induced IL-8 secretion was detected by Western blot. KB cells were pretreated with aloin, and its effect on IL-1β-induced IL-8 production was examined by ELISA and Western blot analysis. Saliva with high IL-1β strongly stimulated IL-8 production in KB cells, and IL-1 receptor agonist significantly inhibited IL-8 production. Low IL-1β-containing saliva did not increase IL-8 production. IL-1β treatment of KB cells induced activation of MAPK signaling molecules as well as nuclear factor-kappa B. IL-1β-induced IL-8 production was decreased by p38 and extracellular signal-regulated kinase (ERK) inhibitor treatment. Aloin pretreatment inhibited IL-1β-induced IL-8 production in a dose-dependent manner and inhibited activation of the p38 and ERK signaling pathway. Finally, aloin pretreatment also inhibited saliva-induced IL-8 production. Results indicated that IL-1β in saliva stimulates epithelial cells to produce IL-8 and that aloin effectively inhibits salivary IL-1β-induced IL-8 production by mitigating the p38 and ERK pathway. Therefore, aloin may be a good candidate for modulating oral inflammatory diseases.

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis.

The microenvironment of follicular lymphoma (FL) is composed of tumor-infiltrating CD8(+) T cells, follicular regulatory T cells, lymphoma-associated macrophages and mast cells, follicular helper T cells, follicular dendritic cells, and follicular reticular cells, all of which have been reported to have relevance in the prognosis of FL patients. In addition, some of these cells play a role in the histologic transformation of FL. Macrophages contribute to a poor prognosis in FL patients treated in the pre-rituximab era, but are associated with good prognosis in those treated in the rituximab era. T-cell immunoglobulin and mucin domain protein (TIM) 3 are markers of T-cell exhaustion, and T cells co-expressing programed death 1 (PD1) in peripheral blood and lymph nodes secrete interleukin (IL)-12 in the serum. Serum CXCL9, IL-2 receptor, and IL-1 receptor agonist are associated with shorter survival of FL patients. Agents for manipulation of the microenvironment surrounding FL cells include the immunomodulatory drug lenalidomide, immune check-point inhibitors, and cyclophosphamide prior to rituximab. To battle FL and to improve the outcomes of FL patients, understanding the relationship between neoplastic cells and the various microenvironmental cellular components is crucial for developing therapeutics against the microenvironment.