Soluble Receptor Levels Research Articles

Biomarkers of inflammation and epithelial barrier function in multiple sclerosis

BackgroundThere is a lack of reliable biomarkers predicting disability and disease activity in multiple sclerosis (MS). Recent evidence suggests an involvement of intestinal and pulmonary epithelial barrier function related to immune activation and the pathophysiology of MS. Blood biomarkers of epithelial barrier function have, however, not been widely studied in MS. ObjectiveTo examine biomarkers of inflammation and epithelial barrier function in relapsing remitting MS (RRMS) patients compared with healthy controls (HCs), and to assess associations between biomarkers and disease activity. MethodsA panel of 30 biomarkers were measured in serum or plasma from 49 newly diagnosed, untreated RRMS patients and 58 HCs with electrochemiluminescence or ELISA. Neurofilament light chain (NfL) was measured with single-molecule array. Validation was performed in a second independent cohort of 68 newly diagnosed, treatment naive RRMS patients and 50 HCs. Patients were divided into groups of active and inactive disease based on NfL levels and the presence of gadolinium enhancing magnetic resonance imaging lesions. ResultsPatients with active MS showed significantly higher serum levels of calprotectin and soluble urokinase plasminogen activator receptor compared with inactive MS in the exploratory cohort. Validation confirmed higher levels of calprotectin in active compared with inactive MS, and HCs. Biomarkers of intestinal and pulmonary epithelial barrier function did not differ significantly between groups. ConclusionsThe measured biomarkers of epithelial barrier function do not seem to play a major role in the pathophysiology of MS, but serum calprotectin could represent a clinically useful biomarker of innate immune activation and disease activity.

Selective Increment of Synovial Soluble TYRO3 Correlates with Disease Severity and Joint Inflammation in Patients with Rheumatoid Arthritis.

Objective To investigate the role of TAM receptors in rheumatoid arthritis (RA) by determining synovial tissue TAM receptor expression, synovial fluid levels of soluble TAM receptors, and the relationship between soluble TAM receptors, joint inflammation and disease activity. Methods TAM receptor expression was determined by immunohistochemistry on the synovium from RA and osteoarthritis (OA) patients. Soluble (s) Tyro3, sAxl, sMer, and their ligand Gas6 were measured by ELISA in the synovial fluid of RA (n = 28) and OA (n = 12) patients and cytokine levels by multiplex immunoassay in RA samples. Correlation analyses were performed among sTAM receptors with local cytokine levels; systemic disease parameters like erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and anticyclic citrullinated peptide antibodies (ACPA); and disease activity scores (DAS28-ESR) in RA patients. Results TAM receptors were expressed on different locations in the synovial tissue (lining, sublining, and blood vessels), and a similar expression pattern was observed in RA and OA patients. Synovial fluid sTyro3 and sMer were significantly enhanced in RA compared to OA patients, whereas no significant differences in sAxl and Gas6 levels were found. In RA samples, sTyro3 levels, but not sMer, correlated positively with proinflammatory local cytokines and the systemic factor erythrocyte sedimentation rate. Moreover, stratification analysis showed high sTyro3 levels positively correlated with higher DAS28-ESR and in RF and ACPA double positive RA patients. Conclusion sTyro3 in the synovial fluid of RA patients correlates with local inflammatory molecules and systemic disease activity. These findings suggest that the reduced negative control of cell activation by TAM receptors due to their shedding in the synovial fluid, mainly sTyro3, favoring joint inflammation in RA patients.

Abnormal Levels of Some Biomarkers of Immune Activation Despite Very Early Treatment of Human Immunodeficiency Virus.

Despite early antiretroviral therapy (ART), ART-suppressed people with human immunodeficiency virus (HIV) (PWH) remain at higher risk for infections and infection-related cancers than the general population. The immunologic pathways that remain abnormal in this setting, potentially contributing to these complications, are unclear. ART-suppressed PWH and HIV-negative controls, all cytomegalovirus seropositive and enriched for HIV risk factors, were sampled from an influenza vaccine responsiveness study. PWH were stratified by timing of ART initiation (within 6 months of infection [early ART] vs later) and nadir CD4+ T-cell count among later initiators. Between-group differences in kynurenine-tryptophan (KT) ratio, interferon-inducible protein 10, soluble CD14 and CD163, soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor were assessed after confounder adjustment. Most participants (92%) were male, reflecting the demographics of early-ART initiators in San Francisco. Most biomarkers were higher among later-ART initiators. Participants in the early-ART group achieved near-normal soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor levels, but substantially higher KT ratio than those without HIV after confounder adjustment (P = .008). Soluble CD14, soluble CD163, and interferon-inducible protein 10 trended similarly. While early-ART initiators restore near-normal levels of many inflammatory markers, the kynurenine pathway of tryptophan catabolism remains abnormally high. Because this pathway confers adaptive immune defects and predicts tuberculosis and cancer progression, this it may contribute to persistent risks of these complications in this setting.

Complements as a Predictive Biomarker of Lupus Nephritis in Female Patients with Systemic Lupus Erythematosus

Background: Lupus nephritis (LN) has been demonstrated in about 40–50 percent of all systemic lupus erythematosus (SLE) patients. Patients having renal flares are at risk from suffering serious kidney damage, and usually have a poor prognosis. Unfortunately, renal flare pathogenesis in LN patients remains unclear, and no known predictions of an impending renal flare exist. Aim: The present study aims to measure circulating levels of anti-C1q antibodies, C3, C4, TNF-α and soluble TNF-α receptor, serum creatinine and blood urea nitrogen (BUN) as biomarkers for active LN. Materials and methods: The study included 180 SLE female patients meeting the revised classification requirements of the modified American College of Rheumatology (ACR); 90 female patients with active proliferative LN (biopsy-proven) and other 90 patients with inactive LN. Patients were receiving mycophenolate mofetil; and the study was conducted between 2018 and 2019. Results: We found that low levels of complement C3 and C4 in combination with high levels of BUN, creatinine, anti-C1q antibodies and positive anti-dsDNA antibodies were more likely to be associated with lupus nephritis development in SLE patients. Also, high levels of TNF-α and its soluble receptor can be used as an indication of active disease activity and flare development. Conclusion: Monitoring of Anti-C1q antibodies, C3, C4, serum creatinine, and BUN levels in SLE patients can improve LN prognosis. TNF-α can also be used as an indicator for active LN and concomitant flare. This early diagnosis combined with prompt care would help decrease morbidity and mortality in LN patients.

Serum biomarkers in patients with stable and exacerbated COPD-bronchiectasis overlap syndrome.

Bronchiectasis (B), commonly seen in patients with chronic obstructive pulmonary disease (COPD), is associated with exacerbations and predicts mortality. To differentiate patient groups with COPD-(B+) or COPD-(B-) and their exacerbations by using inflammatory markers. Consecutive COPD patients were divided into two groups according to findings on high resolution thorax CT (HRCT) images using Smith and modified Reiff scores. Patients were prospectively followed for possible future exacerbations. Serum fibrinogen, C-reactive protein (CRP), soluble urokinase-type plasminogen activator receptor (suPAR) and Plasminogen activator inhibitor-1 (PAI-1) levels were studied during exacerbation and stable periods. Eighty-seven patients were included and (85M, 2 F), mean aged was 68.1±9 (46-87). HRCT confirmed bronchiectasis in 38 (43.7%) patients, most commonly in tubular form (89.4%) and in lower lobes. COPD-B(+) group had lower body mass index (P=0.036), more advanced stage of disease (P=0.004) and more frequent exacerbation (P=0.01). The HRCT scores were correlated with exacerbation rate (r=0.356, P<0.05). Fibrinogen and CRP values were higher in exacerbation (P= 0.01, P= 0.013, respectively) especially in COPD-B(+) patients. suPAR and PAI-1 levels were also higher in COPD-B(+) patients although it was not statistically significant. Bronchiectasis is common and causes frequent exacerbations in COPD. Identifying of COPD-B(+) phenotype by HRCT scoring systems has considerable importance for both therapeutic options and clinical outcome of the disease. In addition to fibrinogen and CRP, high serum levels of suPAR and PAI-1 suggest us their significant roles in increased systemic inflammation associated with coexisting of COPD and bronchiectasis.

Early Post-stroke Depressive Symptoms are Associated with Low Peripheral Levels of Soluble Triggering Receptor Expressed on Myeloid Cells-1 (sTREM-1) and Glial Cell-derived Neurotrophic Factor (GDNF).

Stroke is a major cause of death and disability worldwide. Among its complications, post-stroke depression (PSD) leads to a significant burden. The diagnosis of PSD is complex, and there are no biomarkers that can assist in its early identification and adequate management. The aim of the present study is to investigate peripheral biomarkers in the acute phase of stroke and their potential association with depressive symptoms. We evaluated 60 patients in the acute phase of stroke by using standardized instruments of psychiatric and neurological assessment (Mini International Neuropsychiatric Interview-Plus- MINI-Plus, Hospital Anxiety and Depression Scale-HADS, and National Institutes of Health Stroke Scale-NIHSS) and measured peripheral biomarkers. In multivariate analysis, low peripheral levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and higher NIHSS scores were associated with PSD. The severity of depressive symptoms was inversely correlated with sTREM-1 and glial cell-derived neurotrophic factor (GDNF) levels. This is the first study indicating an association between sTREM-1 and PSD. Our results may point to the involvement of glial mechanisms in the manifestation of depressive symptoms after stroke.

Serum and CSF cytokine levels mirror different neuroimmunological mechanisms in patients with LGI1 and Caspr2 encephalitis

Changes in levels of cytokines or soluble receptors in biological fluids may provide information on immunological pathomechanisms underlying the respective diseases. Here, we studied cytokine patterns of patients with autoimmune encephalitis (AE) before and after immunosuppressive treatment in order to identify possible biomarker candidates and to look for putatively involved pathomechanisms.We performed measurements in Cerebrospinal fluid (CSF) and serum of 7 patients suffering from AE with antibodies (ab) against Leucine-rich glioma-inactivated-protein 1 (LGI1) and 9 AE patients with Contactin-associated protein-like 2 (Caspr2) ab recruited from two tertiary AE centers in Magdeburg and Berlin, Germany. In the Magdeburg samples before and after treatment were available for the measurements and in the Berlin cohort samples were collected after treatment was initiated.First, we used a human cytokine array comprising 36 cytokines or soluble receptors to screen for biomarkers in CSF samples of 8 AE (before and after treatment), 4 herpes-simplex virus meningoencephalitis patients and 4 controls without neuroinflammation. Next, CCL2, CXCl10, CXCl13, Il -6 and sICAM1 were chosen as candidates and measured in CSF and serum with specific ELISA systems in all 16 AE patients, 14 controls without neuroinflammation and 7 herpes-simplex virus meningitis patients. Clinical outcome was assessed via modified Rankin scale. LGI1 and Caspr2 abs from the Magdeburg cohort were purified by chromatography. IgG subclasses of these LGI1 or Caspr2 abs were identified by immunoblot analysis.The levels of most candidate parameters were higher in the CSF of Caspr2 than of LGI1 AE patients and controls, but there were no significant changes of cytokine concentrations before and after initiating treatment. Thus, these parameters seem unsuited as surrogate biomarkers of disease. Significantly higher levels were observed in the CSFs of Caspr2 AE patients (CXCL13 and sICAM1) as well as in the serum of Caspr2 (CXCL10) and LGI1 AE patients (CXCL13) in comparison to control samples.These results suggest that neuro-immunological pathomechanisms may differ between Caspr2 and LGI1 AE patients. Caspr2 AE seems to elicit a higher immune response than LGI1 AE, which has no correlation to the respective IgG subclass combination of AE specific abs involved in each type of disease.

Serum level of soluble urokinase plasminogen activator receptor (suPAR) as a disease severity marker of myasthenia gravis: a pilot study.

Myasthenia gravis (MG) is an autoantibody-mediated inflammatory disease of the neuromuscular junction. Biomarkers indicating disease activity in MG are warranted. Recently, the soluble urokinase plasminogen activator receptor (suPAR) has been reported to be associated with inflammation, tissue damage, disease activity and prognosis in various diseases, including autoimmune diseases. In this study, serum suPAR levels were measured in 40patients with anti-acetylcholine receptor antibody-positive MG and 30controls, and their correlations with clinical variables and severity scale scores were investigated. We identified that serum suPAR levels significantly correlated with MG activities of daily living scale (Spearman's ρ=0·45; P=0·004) and MG Foundation of America classification (Spearman's ρ=0·37; P=0·02) at serum sampling, but not with anti-acetylcholine receptor antibody titers. In conclusion, serum suPAR levels can be a candidate for a novel biomarker of disease activity in anti-acetylcholine receptor antibody-positive MG.

Increased levels of soluble mannose receptor are associated with poor outcome in cirrhosis: results from a 2-year longitudinal study

Increased levels of soluble mannose receptor are associated with poor outcome in cirrhosis: results from a 2-year longitudinal study

Elevated plasma sRAGE and IGFBP7 in heart failure decrease after heart transplantation in association with haemodynamics.

AimsMetabolic derangement is implicated in the pathophysiology of heart failure (HF) and pulmonary hypertension (PH). We aimed to identify the dynamics of metabolic plasma proteins linked to end‐stage HF and associated PH in relation to haemodynamics, before and after heart transplantation (HT).Methods and resultsTwenty‐one metabolic plasma proteins were analysed with proximity extension assay in 20 controls and 26 patients before and 1 year after HT. Right heart catheterizations were performed in the HF patients pre‐operatively and 1 year after HT. Plasma levels of soluble receptor for advanced glycation end products (sRAGE) and insulin‐like growth factor‐binding protein 7 (IGFBP7) were higher in HF patients compared with controls (P < 0.0001) and decreased after HT (P < 0.0001), matching controls' levels. The decrease in sRAGE after HT correlated with improved mean pulmonary arterial pressure (r s = 0.7; P < 0.0001), pulmonary arterial wedge pressure (r s = 0.73; P < 0.0001), pulmonary vascular resistance (r s = 0.65; P = 0.00062), and pulmonary arterial compliance (r s = −0.52; P = 0.0074). The change in plasma IGFBP7 after HT correlated with improved mean right atrial pressure (r s = 0.71; P = 0.00011) and N‐terminal pro‐brain natriuretic peptide (r s = 0.71; P < 0.0001).ConclusionsOur results indicate that plasma sRAGE may reflect passive pulmonary vascular congestion and the ‘mechanical’ state of the pulmonary vasculature in HF patients with or without related PH. Furthermore, sRAGE and IGFBP7 may provide additional insight into the pathophysiological mechanisms in HF and associated PH. Their potential clinical and therapeutic relevance in HF and associated PH need further investigation.

Acupuncture inhibited airway inflammation and group 2 innate lymphoid cells in the lung in an ovalbumin-induced murine asthma model.

Group 2 innate lymphoid cells (ILC2s) are known to serve important functions in the pathogenesis of allergic airway inflammation. Studies have shown that acupuncture has an anti-inflammatory effect in the airways. However, how acupuncture treatment affects innate immunity, especially with regard to the function of ILC2s in ovalbumin (OVA)-induced allergic airway inflammation, is poorly understood. BALB/c mice were injected and subsequently challenged with OVA ± treated with manual acupuncture. At the end of the experimental course, lung function was assessed by measurement of airway resistance (RL) and lung dynamic compliance (Cdyn). Cytokine levels were detected by enzyme-linked immunosorbent assay (ELISA). ILC2 proportions in the lung were analyzed by flow cytometry. The results showed that airway inflammation and mucus secretion were significantly suppressed by acupuncture treatment. RL decreased while Cdyn increased after acupuncture treatment. There was an apparent decrease in the bronchoalveolar lavage fluid (BALF) concentrations of interleukin (IL)-5, IL-13, IL-9, IL-25 and IL-33 and an increase in soluble IL-33 receptor (sST2) levels compared with untreated asthmatic mice. Acupuncture also reduced the lin-CD45+KLRG1+ST2+ cell proportion in the lung. In conclusion, this study has demonstrated that acupuncture treatment alleviates allergic airway inflammation and inhibits pulmonary ILC2 influx and IL-5, IL-9 and IL-13 production. The inhibition of ILC2s by acupuncture may be associated with the IL-33/ST2-signaling pathway and IL-25 levels, thereby offering protection from the respiratory inflammation associated with asthma.

Association between serum soluble (pro)renin receptor level and worsening of cardiac function in hemodialysis patients: A prospective observational study.

The (pro)renin receptor ((P)RR) is cleaved to generate soluble (P)RR (s(P)RR), which reflects the status of the tissue renin-angiotensin system. Hemodialysis (HD) patients have a poor prognosis due to the increased prevalence of cardiovascular diseases. The present study aimed to investigate whether serum s(P)RR level is associated with the worsening of cardiac function in HD patients. A total of 258 maintenance HD patients were recruited and serum s(P)RR concentration was measured. Background factors in patients who survived (S group) and patients who died (D group) during the 12-month follow-up period and relationships between serum s(P)RR level and changes in cardiac function during the follow-up period in the S group were investigated. The median serum s(P)RR value at baseline was 29.8 ng/ml. Twenty-four patients died during the follow-up period. Cardiothoracic ratio, human atrial natriuretic peptide (hANP), brain natriuretic peptide (BNP), and E over e-prime were significantly higher in the D group. In the S group, changes in hANP or BNP were significantly greater in the higher serum s(P)RR group than in the lower serum s(P)RR group. High serum s(P)RR level was significantly correlated with changes in BNP, independent of other factors. High serum s(P)RR level was associated with increases in BNP, independent of other risk factors, suggesting that an increased expression of (P)RR may be associated with a progression of heart failure in HD patients and that serum s(P)RR concentration could be used as a biomarker for selecting patients requiring intensive care.

SUN-607 Iron Parameters in Patients with Partial Lipodystrophy and Impact of Metreleptin Therapy

Introduction Intriguing rodent studies and epidemiological data suggest that iron metabolism and adipocytokines crosstalk to regulate glucose metabolism and fuel storage. Iron parameters have not been previously studied in patients with lipodystrophy whereas increased iron stores have been associated with type 2 diabetes. In this study, we sought to investigate the status of iron parameters in patients with partial lipodystrophy (PL) and to interrogate whether the adipocyte hormone leptin can modulate iron metabolism. Methods Serum samples of 19 patients with PL (age: 42, IQR: 34-57, M/F: 3/16) were used from an open-label study previously performed at the University of Michigan evaluating the efficacy of metreleptin in nonalcoholic steatohepatitis (NCT01679197) to measure ferritin, hepcidin, iron, and transferrin soluble receptor levels. High-sensitivity C-reactive protein (hs-CRP) levels were also determined as broader changes in inflammatory pathways may potentially impact circulating ferritin levels. Results were integrated into an existing database of metabolic parameters. Data are presented as median, IQR. Results At baseline, ferritin levels were positively correlated with fasting glucose (r = 0.533; p = 0.023) and HbA1c (r = 0.510; p = 0.031). During the 6 months of therapy period, HbA1c (9.2%, 7.3-10.3 vs. month-3: 8.6%, 7.7-9.6; p = 0.099; and month-6: 8.5%, 6.8-9.5; p = 0.264), triglyceride levels (346 mg/dL, 240-1771 vs. month-3: 346 mg/dl, 237-479; p = 0.047; and month-6: 295 mg/dl, 207-495; p = 0.091), and hepatic fat (12.7%, 9.8-20.6 vs. month-6: 8.9%, 7.0-11.0; p = 0.031)} decreased. Reductions were observed in serum ferritin after metreleptin treatment (83.23 ng/mL, 76.43-178.97 vs. month-3: 73.79 ng/ml, 68.30-78.59; p = 0.007; and month-6: 61.03 ng/mL, 46.45-157.74; p = 0.004). There was a tendency for hepcidin and iron to be decreased, but this did not reach statistical significance. On the other hand, there were notable reductions in hs-CRP levels at 6 months compared to baseline (2.94 mg/L, 1.30-4.80 vs. 1.6 mg/L, 1.00-6.30; p = 0.012). Baseline leptin level was inversely correlated with percent reduction in hs-CRP at month-6 (r = -0.685; p = 0.001). Also, modest correlations were observed between changes in serum iron and triglycerides (r = 0.491, p = 0.033) and hepatic fat (r = 0.412, p = 0.079). Conclusions We observed a significant relationship between ferritin and glucose control in a group of patients with PL. Metreleptin therapy was associated with improvements in triglycerides and hepatic fat and there were also significant decreases in ferritin and hs-CRP levels. These results raise the possibility that metreleptin therapy influences iron metabolism. However, whether the decrease in ferritin indicates a decrease in iron stores or is mediated by an effect on inflammation remains unknown.

Plasma levels of soluble TNF receptors are associated with cardiac function in patients with Chagas heart disease

BackgroundThe soluble receptors tumor necrosis factor-alpha (sTNFRs) can lead to an increase in the expression of tumor necrosis factor, increasing its detrimental to systemic inflammatory activation in Chagas cardiomyopathy (ChC). However, the correlation between sTNFRs levels, echocardiographic, and functional levels in patients with ChC remains unknown. This study aimed to verify the correlation between the plasma sTNFRs levels, echocardiographic, and NYHA functional levels in patients with ChC. MethodsSixty-four patients with ChD (54 ± 2 years, 44% males, NYHA I-II) were evaluated by anamnesis protocol, echocardiography, and plasma sTNFR1 and sTNFR2 measurement. Linear regression analysis and Student's t-test were used as appropriate. ResultsHigher plasma sTNFR1 and sTNFR2 levels were associate with worse systolic function (R2 = 0.10; p = 0.008 and R2 = 0.44; p < 0.001) and cardiac dilation (R2 = 0.13; p = 0.002 and R2 = 0.43; p < 0.001). Patients with systolic dysfunction and cardiac dilatation had higher sTNFRs levels (p < 0.001). There were no significant differences among NYHA functional classes for both sTNFRs. ConclusionPlasma sTNFR1 and sTNFR2 levels are associated with greater cardiac dilation and poor systolic function in ChC patients.

Type 1 diabetes and hearing loss: Audiometric assessment and measurement of circulating levels of soluble receptor for advanced glycation end products.

We examined the hearing function in adults with and without type 1 diabetes (T1D) to investigate whether an association exists between hearing loss and duration of diabetes, haemoglobin A1C level, diabetes complications and levels of select serum and urinary biomarkers. We measured pure tone audiometry (PTA) thresholds; serum levels of C-reactive protein (CRP), vascular endothelial growth factor (VEGF), soluble receptors for advanced glycation end-product (sRAGE); and urinary isoprostane in 30 adults with T1D (age 43.8 ± 11.4 years). We also measured PTA thresholds in 11 adults without diabetes (age 53 ± 5.5 years). 63.3% of adults with T1D had high-frequency hearing loss. Among adults with T1D, those with hearing loss were older (48.2 vs 36.2 years old, P < .01), had a longer duration of diabetes (30.7 vs 21.2 years, P = .02), a greater prevalence of peripheral neuropathy (57.9 vs 9.1%, P = .02) and significantly lower median levels of sRAGE (1054.27 vs 1306.83 pg/mL, P = .03) compared to those with normal hearing. Adults with T1D between the ages of 40 and 60 years old, who had diabetes for ≥35 years, had significantly higher PTA thresholds at both 500and 8000 Hz than age-matched adults without diabetes. A significant proportion of adults with T1D have high-frequency hearing loss before age of 60 that is positively associated with age, duration of diabetes and presence of peripheral neuropathy. Our results are in support of previous studies suggesting a potential protective role of sRAGE against AGE toxicity and diabetes complications.

Beneficial Effects of Cannabis on Blood-Brain Barrier Function in Human Immunodeficiency Virus.

Human immunodeficiency virus (HIV) infection leads to blood-brain barrier (BBB) dysfunction that does not resolve despite viral suppression on antiretroviral therapy (ART) and is associated with adverse clinical outcomes. In preclinical models, cannabis restores BBB integrity. We studied persons with HIV (PWH) and HIV-negative (HIV-) individuals who had used cannabis recently. We assessed 2 biomarkers of BBB permeability: the cerebrospinal fluid (CSF) to serum albumin ratio (CSAR) and CSF levels of soluble urokinase plasminogen activator receptor (suPAR), a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the BBB. A composite index of the BBB markers was created using principal components analysis. Neural injury was assessed using neurofilament light (NFL) in CSF by immunoassay. Participants were 45 PWH and 30 HIV- individuals of similar age and ethnicity. Among PWH, higher CSF suPAR levels correlated with higher CSAR values (r = 0.47, P < .001). PWH had higher (more abnormal) BBB index values than HIV- individuals (mean ± SD, 0.361 ± 1.20 vs -0.501 ± 1.11; P = .0214). HIV serostatus interacted with cannabis use frequency, such that more frequent use of cannabis was associated with lower BBB index values in PWH but not in HIV- individuals. Worse BBB index values were associated with higher NFL in CSF (r = 0.380, P = .0169). Cannabis may have a beneficial impact on HIV-associated BBB injury. Since BBB disruption may permit increased entry of toxins such as microbial antigens and inflammatory mediators, with consequent CNS injury, these results support a potential therapeutic role of cannabis among PWH and may have important treatment implications for ART effectiveness and toxicity.

S100A12 promotes inflammation and cell apoptosis in sepsis-induced ARDS via activation of NLRP3 inflammasome signaling

Sepsis is a multiple organ dysfunction elicited by the dysregulated host immune response to microbial infection. Acute respiratory distress syndrome (ARDS) is a serious and acute inflammatory lung injury resulting from sepsis and other severe diseases. The present study aims to investigate the role of S100A12, a pro-inflammatory factor, in the pathophysiologic mechanism underlying the process in sepsis-induced ARDS. In present study, Hematoxylin and Eosin (H&E) Staining was performed to observe pathological changes. Enzyme-Linked Immunosorbent Assay (ELISA) was employed to analyze the levels of inflammatory cytokines. Western blot, immunohistochemistry (IHC) staining and reverse-transcriptase quantitative real-time PCR (RT-qPCR) were performed to determine target gene and protein expression. TUNEL assay and flow cytometry were performed to assay cell apoptosis. We found that the levels of S100A12 and soluble receptor for advanced glycation end-products (sRAGE) are upregulated in the serum of patients with Sepsis-induced ARDS and sepsis mice. Furthermore, higher cell apoptosis rate was observed in lung tissue of sepsis mice. In addition, S100A12 resulted in excessive mucins and the secretion of inflammatory cytokines secretion, and promoted the expression of chemokines and cell adhesion molecules via activating nucleotide-binding oligomerization domain (Nod) -like receptor (NLR) P3 inflammasome pathway in NHBE cells. Finally, S100A12 increased oxidative stress status and cell apoptosis in NHBE cells. Generally, the present study provides evidence that S100A12 is closely related to pathogenesis of sepsis-induced ARDS. Hence, S100A12 may be a useful biomarker of pulmonary injuries for clinical diagnosis of sepsis-induced ARDS.

Dual role of IL6 mediated by mesenchymal stromal cell signaling to joint macrophages in osteoarthritis

Purpose: Osteoarthritis (OA) is a joint disease affecting > 5 million Canadians and patients have limited palliative and joint-replacement surgical options. Stromal cell therapy is emerging as a compelling treatment for OA. Our group led the first-in-Canada Ph1/2 trial with bone marrow mesenchymal stromal cells (BM-MSCs) in OA patients successfully; and significant improvements in patient outcomes were observed. This was accompanied with reduction in pro-inflammatory monocytes/macrophages (MΦs) in the synovial fluid (SF), suggestive of a clinical MSC anti-inflammatory effect. Understanding mechanism of action of MSCs in OA will enable effective donor MSC screening, and generation of more efficient engineered MSCs. While IL6 is a known pro-inflammatory mediator in the joint, and anti-IL6 therapeutics have been effective in treatment of Rheumatoid Arthritis, blocking single pro-inflammatory cytokines has been less effective in OA. This leads us to believe that IL6 might have complex roles. Indeed, MSCs-induced polarization of macrophages to inflammation resolving subtypes via IL6 signaling. This effect is not well studied in an OA joint where high levels of IL6 may have pro-inflammatory effects. We hypothesize that IL-6, which is known as pro-inflammatory mediator in OA is mediating anti-inflammatory function of MSCs through signaling via membrane-bound, but not soluble receptors. Methods: We co-cultured peripheral blood-derived MΦs with OA BM-MSCs in the presence of early and late SF from OA patients; or in the presence of IL6 antibody. Polarization of MΦs were assessed by analysis of surface markers and IL10 secretion. Levels of IL6 soluble IL6 receptor (sIL6R) were measured by ELISA. Results: Preliminary quantification of BM- MSC from OA patients revealed high IL6 secretion is associated with positive patient-reported outcomes. IL6 antibody abrogated MSCs-induced anti-inflammatory polarization of MΦs as shown by reduction of CD163 and CD206, suggesting a key role for IL6 in MSC anti-inflammatory effects on MΦs. Paradoxically, IL6 levels were increased in SF from late stage OA, whereas levels of sIL6R were comparable in early and late OA-SF. Further, the effect of MSCs on anti-inflammatory polarization of MΦs was attenuated in the presence of late OA-SF compared to early OA-SF. This could be due to enhanced IL6 trans-signaling (mediated by sIL6R) in late-stage OA SF expected to occur at the expense of reduced IL6 classical pathway (mediated by membrane bound IL6 receptor, mIL6R). To discriminate between classical vs. trans-signalling, we are using soluble gp130, a non-signaling decoy receptor which complexes IL6-sIL6R. Our preliminary result showed that sgp130 treatment enhanced the expression of CD163 in MΦs exposed to pooled OA SF. The classical IL6 pathway will be studied specifically by silencing mIL6R in MΦs using siRNA Conclusions: MSCs exert their anti-inflammatory action in OA, at least partly through polarization of MΦs to anti-inflammatory phenotype mediated by IL6. The ratio of IL6 signaling through trans-vs. classical signaling pathways is an important arbiter of MSC-modulation of joint inflammation.

Эндотоксиновый компонент патогенеза ВИЧ-инфекции

Механизм прогрессирования иммуносупрессии при ВИЧ-инфекции не может быть сведен лишь к гибели CD4+ лимфоцитов вследствие репликации в них вируса. Полученные в результате многочисленных исследований данные свидетельствуют о важной роли избыточной активации иммунной системы в патогенезе заболевания. В качестве одного из факторов, поддерживающих активацию иммунной системы и развитие у ВИЧ-инфицированных разной степени проявлений системного воспалительного ответа, рассматривается эндотоксин (ЭТ) грамотрицательных бактерий. Роль эндотоксина в этом процессе подтверждается высокими показателями эндотоксина и растворимого рецептора CD14 в крови, а также изменениями уровня эндотоксин-связывающих антител у большей части больных с ВИЧ-инфекцией, находящихся на разных стадиях заболевания. Поступлению избыточных количеств эндотоксина в кровоток способствует повреждение кишечной стенки, характерное для течения ВИЧ-инфекции с самого начала заболевания, наблюдающееся в течение всей жизни пациента, и не купирующееся полностью на фоне антиретровирусной терапии (АРВТ). Определенный вклад в микробную транслокацию могут вносить и нарушения микробиоценоза кишечника, так же весьма характерные для течения ВИЧ-инфекции. Продолжение исследований в данном направлении позволит разработать методы патогенетической терапии, которые в сочетании с АРВТ смогут повысить эффективность лечебных мероприятий и увеличить продолжительность жизни пациентов. The mechanism of immunosuppression progression in HIV infection cannot be reduced only to destruction of CD4+ lymphocytes due to the virus replication. Multiple studies have stressed an important role of immune system overactivation in the pathogenesis of the disease. Endotoxin of gram-negative bacteria is considered as one of the factors supporting the immune system activation and manifestations of the systemic inflammatory response of different severity in HIV-infected people. This fact is confirmed by high levels of endotoxin and soluble CD14 receptor as well as by changes in endotoxin-binding antibody titers in a vast majority of patients with HIV infection at different stages of the disease. Excessive amounts of endotoxin release into the blood due to damage of the intestinal wall, which is typical for the course of HIV infection from the disease onset throughout the patient’s life and cannot be completely reversed by antiretroviral therapy (ART). Disorders of the intestinal microbiocenosis, which are also very typical for the HIV infection, can also contribute to the microbial translocation. Further studies in this direction will allow developing methods for pathogenetic therapy, which in combination with ART would increase the effectiveness of therapeutic measures and prolong the life expectancy of patients.

Rifaximin Alleviates Endotoxemia with Decreased Serum Levels of Soluble CD163 and Mannose Receptor and Partial Modification of Gut Microbiota in Cirrhotic Patients.

Rifaximin is a poorly absorbable antibiotic against hepatic encephalopathy (HE). This observational study aimed to elucidate the effect of rifaximin on intestinal permeability and gut microbiota in patients with decompensated cirrhosis. Thirty patients with decompensated cirrhosis were assessed by ammonia level, neuropsychological testing, endotoxin activity (EA), and serum proinflammatory cytokines at baseline and after four weeks of rifaximin treatment (1200 mg/day). Intestinal permeability was indicated by serum soluble CD163 (sCD163), mannose receptor (sMR), and zonulin levels. To evaluate the gut microbiome, 16S ribosomal RNA gene sequencing was applied. Rifaximin ameliorated hyperammonemia and cognitive dysfunction, although it did not change the serum proinflammatory cytokine levels. It decreased EA levels as well as serum levels of sCD163 and sMR, but not zonulin, and both decreases in sCD163 and sMR showed positive correlations with EA decrease (ΔsCD163: Correlation coefficient (R) = 0.680, p = 0.023; ΔsMR: R = 0.613, p = 0.014, vs. ΔEA). Gut microbial analysis revealed that the richness and complexity of species were unchanged while the abundance of the Streptococcus genus was reduced after treatment with rifaximin. Collectively, rifaximin alleviated HE and endotoxemia with improved intestinal hyperpermeability in patients with decompensated cirrhosis, and this effect is partially involved in a gut microbial change.