The Role of Soluble CD163 (sCD163) in Human Physiology and Pathophysiology.

Soluble CD163 (sCD163) is a circulating inflammatory mediator, indicative of acute and chronic, systemic and non-systemic inflammatory conditions. It is the cleavage outcome, consisting of almost the entire extracellular domain, of the CD163, a receptor expressed in monocytic lineages. Its expression is proportional to the abundance of CD163+ macrophages. Various mechanisms trigger the shedding of the CD163 receptor or the accumulation of CD163-expressing macrophages, inducing the sCD163 concentration in the circulation and bodily fluids. The activities of sCD163 range from hemoglobin (Hb) scavenging, macrophage marker, decoy receptor for cytokines, participation in immune defense mechanisms, and paracrine effects in various tissues, including the endothelium. It is an established marker of macrophage activation and thus participates in many diseases, including chronic inflammatory conditions, such as atherosclerosis, asthma, and rheumatoid arthritis; acute inflammatory conditions, such as sepsis, hepatitis, and malaria; insulin resistance; diabetes; and tumors. The sCD163 levels have been correlated with the severity, stage of the disease, and clinical outcome for many of these conditions. This review article summarizes the expression and role of sCD163 and its precursor protein, CD163, outlines the sCD163 generation mechanisms, the biological activities, and the known underlying molecular mechanisms, with an emphasis on its impact on the endothelium and its contribution in the pathophysiology of human diseases.

Circulating soluble CD163 is associated with reduced Glasgow Coma Scale Score and 1-year all-cause mortality in traumatized patients.

Soluble CD163 (sCD163) is a biomarker of macrophage activation, not previously investigated in the circulation of traumatized patients. A biobank of 398 adult trauma patients was analyzed. Patients with an Injury Severity Score (ISS) >8 served as trauma patients (n = 195) and those with ISS ≤8 as trauma controls (n = 203). Serum samples obtained upon admission, 15h and 72h after were analyzed for sCD163 using an in-house ELISA. Multiple linear regression was used to analyze the association between admission levels of sCD163 with, 1: overall trauma severity (ISS), and 2: severity of injury to specified organs using Abbreviated Injury Score (AIS) and Glasgow Coma Scale (GCS). The association between the peak level of sCD163 with 1-year all-cause mortality was analyzed by logistic regression analysis. Median admission levels of sCD163 were higher in trauma patients than trauma controls [2.32 (IQR 1.73 to 2.86) vs. 1.92 (IQR 1.41 to 2.51) mg/L, p < 0.01]. Worsening GCS score was associated with a 10.3% (95% CI: 17.0 to 3.1, p < 0.01) increase in sCD163. Increasing Head-AIS score was associated with a 5.1% (95% CI: -0.5 to 11.0, p = 0.07) increase in sCD163. The remaining AIS scores and ISS were not consistently associated with sCD163 admission levels. Each mg/L increase in sCD163 peak level had an odds ratio 1.34 (95%CI: 0.98 to 1.83), p = 0.06) after adjustment for age, sex, and GCS. Circulating sCD163 is increased in traumatized patients and associated with worsening GCS. Our findings suggest an association between circulating sCD163 levels with 1-year all-cause mortality.

Clinical significance of serum soluble scavenger receptor CD163 in patients with lupus nephritis.

BACKGROUND: The soluble CD163 (sCD163) was elevated in systemic lupus erythematosus (SLE) patients. PURPOSE: To study whether serum sCD163 could be used to predict the occurrence and prognosis of lupus nephritis (LN). RESEARCH DESIGN: The recruited patients were classified into different groups according to standard identification criteria. STUDY SAMPLE: The patients with LN. DATA COLLECTION AND ANALYSIS: 11 indices were analyzed and compared in SLE and LN patients. Furthermore, the level of serum sCD163 was detected using an enzyme-linked immunosorbent assay. Meanwhile, the receiver operating characteristic analysis was performed to evaluate the prediction effect of sCD163. Additionally, spearman correlation analysis of serum sCD163 with indices was conducted. RESULTS: There were six positive indices and one negative risk factor correlated to LN. sCD163 was elevated in LN patients and could be used to diagnose LN. Importantly, sCD163 was increased in LN patients with a heavy SLE disease activity index. Finally, it was revealed that the level of sCD163 was higher in the LN patients with no response than that with complete or partial response, which also could predict the prognosis of LN. CONCLUSIONS: Serum sCD163 was elevated in LN patients than in SLE patients, which could be used to predict the occurrence and prognosis of LN.

Inflammatory Biomarkers to Predict Major Adverse Cardiovascular Events in Patients with Carotid Artery Stenosis.

Background and Objectives: Inflammatory proteins and their prognostic value in patients with carotid artery stenosis (CAS) have not been adequately studied. Herein, we identified CAS-specific biomarkers from a large pool of inflammatory proteins and assessed the ability of these biomarkers to predict adverse events in individuals with CAS. Materials and Methods: Samples of blood were prospectively obtained from 336 individuals (290 with CAS and 46 without CAS). Plasma concentrations of 29 inflammatory proteins were determined at recruitment, and the patients were followed for 24 months. The outcome of interest was a major adverse cardiovascular event (MACE; composite of stroke, myocardial infarction, or death). The differences in plasma protein concentrations between patients with vs. without a 2-year MACE were determined using the independent t-test or Mann-Whitney U test to identify CAS-specific prognostic biomarkers. Kaplan-Meier and Cox proportional hazards analyses with adjustment for baseline demographic and clinical characteristics were performed to assess the prognostic value of differentially expressed inflammatory proteins in predicting a 2-year MACE in patients with CAS. Results: The mean age of the cohort was 68.8 (SD 10.2) years and 39% were female. The plasma concentrations of two inflammatory proteins were significantly higher in individuals with a 2-year MACE relative to those without a 2-year MACE: IL-6 (5.07 (SD 4.66) vs. 3.36 (SD 4.04) pg/mL, p = 0.03) and CD163 (233.825 (SD 230.306) vs. 159.673 (SD 175.669) pg/mL, p = 0.033). Over a follow-up period of 2 years, individuals with elevated levels of IL-6 were more likely to develop MACE (HR 1.269 (95% CI 1.122-1.639), p = 0.042). Similarly, over a 2-year period, patients with high levels of CD163 were more likely to develop MACE (HR 1.413 (95% CI 1.022-1.954), p = 0.036). Conclusions: The plasma levels of inflammatory proteins IL-6 and CD163 are independently associated with adverse outcomes in individuals with CAS. These CAS-specific prognostic biomarkers may assist in the risk stratification of patients at an elevated risk of a MACE and subsequently guide further vascular evaluation, specialist referrals, and aggressive medical/surgical management, thereby improving outcomes for patients with CAS.

Structural Determinants of Health and Markers of Immune Activation and Systemic Inflammation in Sexual Minority Men With and Without HIV.

Among sexual minority men (SMM), HIV and use of stimulants such as methamphetamine are linked with immune activation and systemic inflammation. Throughout the COVID-19 pandemic, SMM encountered financial challenges and structural obstacles that might have uniquely contributed to immune dysregulation and systemic inflammation, beyond the impacts of HIV and stimulant use. Between August 2020 and February 2022, 72 SMM with and without HIV residing in South Florida enrolled in a COVID-19 prospective cohort study. Multiple linear regression analyses examined unemployment, homelessness, and history of arrest as structural correlates of soluble markers of immune activation (i.e., sCD14 and sCD163) and inflammation (i.e., sTNF-α receptors I and II) at baseline after adjusting for HIV status, stimulant use, and recent SARS-CoV-2 infection. Enrolled participants were predominantly Latino (59%), gay-identified (85%), and with a mean age of 38 (SD, 12) years with approximately one-third (38%) of participants living with HIV. After adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use, unemployment independently predicted higher levels of sCD163 (ß = 0.24, p = 0.04) and sTNF-α receptor I (ß = 0.26, p = 0.02). Homelessness (ß = 0.25, p = 0.02) and history of arrest (ß = 0.24, p = 0.04) independently predicted higher levels of sCD14 after adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use. Independent associations exist between structural barriers and immune activation and systemic inflammation in SMM with and without HIV. Future longitudinal research should further elucidate complex bio-behavioral mechanisms linking structural factors with immune activation and inflammation.

Urinary soluble CD163 is a putative non-invasive biomarker for primary sclerosing cholangitis.

Soluble CD163 (sCD163) is a selective marker of macrophages whose circulating levels have been found to be induced in patients with active inflammatory bowel disease (IBD). Urinary proteins are emerging as non-invasive diagnostic biomarkers, and here, sCD163 levels were measured in the urine of 18 controls and 63 patients with IBD by enzyme-linked immunosorbent assay. Urinary sCD163 levels did, however, not differentiate IBD patients from controls. Analysis of sCD163 in the serum of 51 of these patients did not show higher levels in IBD. Primary sclerosing cholangitis (PSC) is often associated with IBD, and sCD163 was higher in the urine of the 21 patients and in the serum of the 13 patients with PSC compared to patients with IBD. Of clinical relevance, urinary sCD163 levels were higher in PSC patients compared to those with other chronic liver diseases (n = 16), while serum sCD163 levels were comparable between the two groups. Serum sCD163 of IBD and PSC patients positively correlated with serum C-reactive protein. Serum creatinine and glomerular filtration rate, surrogate markers for renal function, did not significantly correlate with urinary or serum sCD163 levels in IBD or PSC patients. Moreover, urinary sCD163 was not related to fecal calprotectin levels whereas serum sCD163 of IBD patients showed a positive trend. PSC associated with IBD and PSC without underlying IBD had similar levels of urinary sCD163 while serum sCD163 tended to be higher in the latter group. In PSC patients, urinary sCD163 did not correlate with serum aminotransferase levels, gamma glutamyl transferase, alkaline phosphatase, bilirubin or the Model for End Stage Liver Disease score. Ursodeoxycholic acid was prescribed to our PSC patients and fecal levels of ursodeoxycholic acid and its conjugated forms were increased in PSC compared to IBD patients. Otherwise, fecal bile acid levels of IBD and PSC patients were almost identical, and were not correlated with urinary and serum sCD163 in PSC. In summary, our study identified urinary sCD163 as a potential biomarker for PSC.

Galectin-3, Galectin-9, and Interleukin-18 Are Associated with Monocyte/Macrophage Activation and Turnover More so than Simian Immunodeficiency Virus-Associated Cardiac Pathology or Encephalitis.

Despite antiretroviral therapy (ART), people living with HIV (PLWH) are at increased risk of developing cardiovascular disease (CVD) and HIV-associated neurocognitive disorder (HAND), among other comorbidities. Studies from ART-treated individuals identified galectin-3 (gal-3) and interleukin (IL)-18 as CVD biomarkers, galectin-9 (gal-9) as a HAND biomarker, and sCD163, a marker of monocyte/macrophage activation, as a biomarker of both. We asked if plasma gal-3, gal-9, and IL-18 are associated with an individual comorbidity or increase in both with animals that develop AIDS with both pathologies versus (CVD-path) alone or simian immunodeficiency virus encephalitis (SIVE) alone. We found that no biomarkers were selective between individual pathologies, and all biomarkers increased with co-development of CVD-path and SIVE (gal-3, p = 0.11; gal-9, p = 0.001; IL-18, p = 0.007; sCD163, p < 0.001; %BrdU p = 0.02). Although gal-3, gal-9, and IL-18 did not distinguish between pathologies, they correlated strongly with one another, with sCD163, a marker of monocyte/macrophage activation, and the %BrdU monocytes, a marker of monocyte turnover. Compared to animals with CVD-path or SIVE alone, animals that co-developed both pathologies had consistently elevated IL-18 throughout infection (p = 0.02) and increased sCD163 in late infection (p = 0.01). These data indicate that gal-3, gal-9, and IL-18 are associated with monocyte/macrophage activation by sCD163 and monocyte turnover by the %BrdU+ monocytes more so than CVD-path or SIVE.

Macrophage activation markers are associated with infection and mortality in patients with acute liver failure.

BACKGROUND AND AIMS: Acute liver failure is a multisystem disorder with a high mortality and frequent need for emergency liver transplantation. Following massive innate immune system activation, soluble markers of macrophage activation are released during liver damage and their association with disease severity and prognosis requires exploration. METHODS: Patients ALF from the United States Acute Liver Failure Study Group (USALFSG, n = 224) and King's College Hospital (n = 40) together with healthy controls (HC, n = 50) were recruited. Serum from early (Days 1-3) and late (>Day 3) time points were analysed for MAMs by enzyme-linked immunosorbent assay correlated to markers of illness severity and 21-day spontaneous survival. Surface expression phenotyping was performed via Flow Cytometry on CD14+ monocytes. RESULTS: All MAMs serum concentrations were significantly higher in ALF compared to controls (p < .0001). sCD206 concentration was higher in early and late stages of the disease in patients with bacteraemia (p = .002) and infection in general (p = .006). In MELD-adjusted multivariate modelling, sCD206 and sCD163 were independently associated with mortality. CD14+ monocyte expression of CD206 (p < .001) was higher in patients with ALF compared with controls and correlated with SOFA score (p = .018). sCD206 was independently validated as a predictor of infection in an external cohort. CONCLUSIONS: sCD206 is increased in serum of ALF patients with infections and poor outcome and is upregulated on CD14+ monocytes. Later measurements of sCD163 and sCD206 during the evolution of ALF have potential as mechanistic predictors of mortality. sCD206 should be explored as a biomarker of sepsis and mortality in ALF.

Soluble Factors CD14, CD163, and Migration Inhibitory Factor Are Associated with Endometriosis-Related Infertility.

OBJECTIVES: Myeloid cell-derived factors contribute to the immunopathology of endometriosis. Soluble CD14 (sCD14), CD163 (sCD163), and MIF serve as in vivo markers of myeloid function. However, these soluble molecules are largely unexplored in women with endometriosis-related infertility cases. We investigated three soluble markers, namely sCD14, sCD163, and MIF, in cases of infertility associated with endometriosis and correlated its level to the stage of endometriosis. DESIGN: Eighty-seven women newly diagnosed with endometriosis or other benign gynecologic control cases linked to infertility were prospectively recruited and underwent diagnostic laparoscopy. PARTICIPANTS: Forty-four patients with endometriosis were included in this study, comprising 19 patients with early-endometriosis (stages I and II) and 25 late-endometriosis (stages III and IV) based on the revised American Society for Reproductive Medicine (rASRM) classification. The remaining 43 patients constituted a control group with infertility due to other causes. METHODS: The levels of sCD14, sCD163, and MIF in serum and peritoneal fluid were assessed using ELISA. RESULTS: Endometriosis women exhibited significantly higher serum levels of sCD163 and MIF levels compared to the control group. Both sCD163 and MIF levels displayed a positive correlation with the rASRM adhesion score. Moreover, the MIF level in serum had a positive correlation with the rASRM endometriosis score. In receiver operating characteristic analysis, serum sCD163 and MIF could significantly discriminate endometriosis and non-endometriosis in infertility cases. LIMITATIONS: Some limitations of the current study deserve to be underlined. First, the sensitive ELISA method was the sole-validated tool for detecting the markers in patient samples. Second, healthy or fertile women were not involved as the control group. CONCLUSIONS: The elevated systemic levels of sCD163 and MIF correlated with the severity of endometriosis. These soluble molecules have a potential diagnostic capacity as a non-invasive biomarker. Furthermore, our data warrants future studies on the underlying mechanism of sCD163 and MIF in endometriosis-related infertility.

Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus.

BACKGROUND: The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. METHOD: Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13). RESULTS: At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group. CONCLUSION: Weight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

Imprinted immune abnormalities in liver transplant patients cured of hepatitis C with antiviral drugs.

Chronic HCV infection induces interferon and dysregulates immune responses through inflammation and chronic antigenic stimulation. Antiviral drugs can cure HCV, providing a unique opportunity to examine the immunological restoration that does and does not occur when a chronic viral infection is eradicated. We quantified blood cytokines levels and used mass cytometry to immunophenotype peripheral blood mononuclear cells before and after HCV cure in 2 groups of patients and controls. At baseline, serum interferon α and soluble CD163 (a macrophage product) were elevated in both liver transplant and nonliver transplant patients compared to controls; the frequencies of several peripheral blood mononuclear cell populations differed from controls; and programmed death protein 1-positivity was increased in nearly all T cell subsets. Many abnormalities persisted after HCV cure, including elevated programmed death protein 1 expression on CD4 naïve and central memory T cells, elevated soluble CD163, and expansion of the plasmablast/plasma cell compartment. Several myeloid-lineage subsets, including Ag-presenting dendritic cells, remained dysregulated. In mechanistic studies, interferon α treatment increased programmed death protein 1 on human T cells and increased T cell receptor signaling. The data identify immunological abnormalities that persist after curative HCV treatment. Before cure, high levels of interferon α may stimulate programmed death protein 1 expression on human T cells, causing persistent functional changes.

Interstitial lung disease progression in patients with anti-aminoacyl transfer-RNA-synthetase autoantibodies is characterized by higher levels of sCD163.

BACKGROUND: Patients with anti-tRNA autoantibodies are characterized by arthritis, mechanic´s hands, fever, Raynaud´s phenomenon, and interstitial lung disease (ILD), in at least two clinical scenarios: the antisynthetase syndrome (ASSD) and interstitial pneumonia with autoimmune features (IPAF). The anti-tRNA-ILD treatment is centered on the administration of corticosteroids and a wide variety of immunosuppressive drugs; however, the effectiveness of the treatment depends on factors not fully understood. This research work aimed to quantify the serum levels of two molecules related to pulmonary fibrosis and explore their relationship with the progression of ILD associated with ASSD METHODOLOGY: Serum levels of sCD163 and TGF-ß1 from baseline and after six months of treatment of ILD patients' positives to anti-tRNA were included in the current study. At six months, patients were classified as with or without ILD progression RESULTS: Forty patients were included (anti-Jo1, anti-PL7, anti-PL12, and anti-Ej). Five patients (12.5%) had ILD progression and were characterized by higher levels of sCD163 at baseline. Baseline sCD163 serum levels showed good discriminatory capacity in patients with ILD progression. On the other hand, at follow-up, serum TGF-ß1 levels significantly increased in both patients' groups, with and without progression CONCLUSION: Basal levels of sCD163 were higher in patients who later developed ILD progression and kinetics of both molecules suggests the participation of M2 macrophages in the development of ILD.

The impact of probiotic yogurt versus ordinary yogurt on serum sTWEAK, sCD163, ADMA, LCAT and BUN in patients with chronic heart failure: a randomized, triple-blind, controlled trial.

BACKGROUND: To date, no study has investigated the effects of probiotic yogurt as a functional food in patients with chronic heart failure (CHF). Therefore, the aim of this study was to compare the impact of probiotic yogurt versus ordinary yogurt on inflammatory, endothelial, lipid and renal indices in CHF patients. In this randomized, triple-blind clinical trial, 90 patients with CHF were randomly allocated into two groups to take either probiotic or ordinary yogurt for 10 weeks. Serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), soluble cluster of differentiation 163 (sCD163), asymmetric dimethylarginine (ADMA), and lecithin cholesterol acyltransferase (LCAT) were measured by using ELISA kits, and blood urea nitrogen (BUN) was measured by calorimetry method at baseline and at the end of trial. The P-value <0.05 was defined as statistically significant. RESULTS: Seventy-eight patients completed the study. At the end of the intervention, the levels of sTWEAK in both groups increased significantly, and this increase was greater in the probiotic yogurt group [691.84 (335.60, 866.95)] compared to control group [581.96 (444.99, 929.40)], and the difference between the groups was statistically significant after adjusting for confounders (P-value: 0.257, adjusted P-value: 0.038). However, no significant differences were found between the groups in the cases of other study indices. CONCLUSION: Probiotic yogurt may be useful for improving the inflammatory status in patients with CHF through increasing sTWEAK levels, however, further studies are needed in this area. © 2022 Society of Chemical Industry.

Complex biological patterns of soluble cytokines and CD163 in childhood necessitating age-specific reference intervals for evidence-based clinical interpretation.

BACKGROUND: Cytokine measurements to support clinical laboratory and research investigations have become increasingly common in pediatrics. However, there is a paucity of accurate pediatric reference intervals (RIs) essential to the interpretation of cytokine results. To address this gap, here, we establish age- and sex-specific pediatric reference values for clinically relevant inflammatory markers including CD163, and the cytokines IL-1ß, IL-6, IL-10, IL-18, TNF-α, IFN-γ, and CXCL-9. METHODS: Healthy children and adolescents (n = 311, 1-19 years) were recruited as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) study. Multi-analyte measurements in plasma and analytical performance verification were conducted on the ProteinSimple® Ella™ automated immunoassay platform (Bio-Techne, MN, USA). Age- and sex-specific RIs were calculated based on Clinical and Laboratory Standards Institute guidelines. Additionally, 75th and 95th percentile cut-offs were determined. RESULTS: Three types of reference value distributions were observed: (a) consistent levels throughout age and sex: IL-6, and IFN-γ, (b) gradual decline in concentration with age: CD163, TNF-α, CXCL-9, and IL-10, (c) significantly higher concentrations during ages 4-14 years than earlier and later ages: IL-1ß and IL-18. Reference values for CXCL-9, IL-10, and TNF-α under 8 years of age differed significantly from older children. CD163, IL-18 and IL-1ß required three age partitions. CD163 demonstrated significant sex differences in ages 8-13 years. CONCLUSION: The circulating profile of cytokines in children is complex and can vary by age and sex. This necessitates careful interpretation of test results based on age and/or sex specific RIs facilitating more accurate clinical decision making.

Effect of hydroxyurea therapy on intravascular hemolysis and endothelial dysfunction markers in sickle cell anemia patients.

Intravascular hemolysis (IH) contributes to the development of endothelial dysfunction (ED) in sickle cell anemia (SCA), and the effects of hydroxyurea (HU, the only approved drug that decreases the frequency and severity of vaso-oclussive crises) on IH and ED in SCA remain unclear. We evaluated and compared the markers of IH among steady-state adult Brazilians with SCA and HbAA individuals. Overall, this cross-sectional study enrolled 30 SCA patients not receiving HU therapy (HbSS), 25 SCA patients receiving HU therapy (HbSS_HU), and 32 HbAA volunteers (HbAA). The IH markers evaluated were serum Lactate Dehydrogenase (LDH), total heme, plasma hemoglobin (pHb), and soluble CD163 (sCD163). The ED markers analyzed were plasma von Willebrand factor (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo) levels, antigen of VWF-cleaving protease (ADAMTS13:Ag), thrombospondin-1, endothelin-1 levels, and ADAMTS13 Activity (ADAMTS13:Act). The levels of VWF:Ag, VWF:RCo, total heme, thrombospondin-1, and endothelin-1 were significantly higher in SCA patients (HbSS and HbSS_HU) compared to HbAA individuals. Also, pHb, LDH, and thrombospondin-1 levels were significantly higher in the HbSS group than in the HbSS_HU group. Contrarily, the levels of sCD163, ADAMTS13:Ag, and ADAMTS13:Act were significantly lower in both groups of SCA patients than HbAA controls, and ADAMTS13:Act levels were significantly lower in HbSS compared to HbSS_HU patients. The higher ADAMTS13 activity levels in those on HU therapy may be attributed to lower pHb and thrombospondin-1 levels as previously shown by in vitro studies that thrombospondin-1 and pHb are bound to VWF. Thus, VWF is restrained from ADAMTS13 activity and cleavage.

CD163 as a Potential Biomarker of Monocyte Activation in Ischemic Stroke Patients.

In ischemic stroke patients, a higher monocyte count is associated with disease severity and worse prognosis. The complex correlation between subset phenotypes and functions underscores the importance of clarifying the role of monocyte subpopulations. We examined the subtype-specific distribution of the CD163+ and CD80+ circulating monocytes and evaluated their association with the inflammatory status in 26 ischemic stroke patients and 16 healthy controls. An increased percentage of CD163+/CD16+ and CD163+/CD14++ events occurred 24 and 48 h after a stroke compared to the controls. CD163+ expression was more pronounced in CD16+ non-classical and intermediate monocytes, as compared to CD14+ classical subtype, 24 h after stroke. Conversely, the percentage of CD80+/CD16+ events was unaffected in patients; meanwhile, the percentage of CD80+/CD14+ events significantly increased only 24 h after stroke. Interleukin (IL)-1beta, TNF-alpha, and IL-4 mRNA levels were higher, while IL-10 mRNA levels were reduced in total monocytes from patients versus controls, at either 24 h or 48 h after stroke. The percentage of CD163+/CD16+ events 24 h after stroke was positively associated with NIHSS score and mRS at admission, suggesting that stroke severity and disability are relevant triggers for CD163+ expression in circulating CD16+ monocytes.

Siglec-7 is an indicator of natural killer cell function in acute myeloid leukemia.

Immune dysfunction is an established risk factor in acute myeloid leukemia (AML). The cytotoxicity of natural killer (NK) cells is greatly impaired in AML, and the profile of NK cell receptors is markedly altered in AML; however, this is not yet well characterized. In this study, we found the downregulation of Siglec-7 could be utilized as a potential marker of NK cell dysfunction in AML. The absolute numbers and percentages of NK cells were declined in the peripheral blood of patients with AML, and the levels of activating receptors NKG2D, NKp46, and NKp30 were reduced in NK cells from patients with AML compared with healthy controls. In contrast, the levels of inhibitory receptors TIM-3, ILT-4, ILT-5, and PD-1 were increased in NK cells from patients with AML. Of note, the level of Siglec-7 in NK cells from patients with AML was significantly lower than that in NK cells from healthy controls, and Siglec-7+ NK cells displayed higher levels of activating receptors and stronger cytotoxicity when compared with Siglec-7- NK cells. Our data indicate that decreased Siglec-7 level may predict NK cell dysfunction in AML, and NK cells may be promising targets of immunotherapy for AML.

S100A9/CD163 expression profiles in classical monocytes as biomarkers to discriminate idiopathic pulmonary fibrosis from idiopathic nonspecific interstitial pneumonia.

Circulating monocytes have pathogenic relevance in idiopathic pulmonary fibrosis (IPF). Here, we determined whether the cell surface levels of two markers, pro-inflammatory-related S100A9 and anti-inflammatory-related CD163, expressed on CD14strongCD16- classical monocytes by flow cytometry could discriminate IPF from idiopathic nonspecific interstitial pneumonia (iNSIP). Twenty-five patients with IPF, 25 with iNSIP, and 20 healthy volunteers were prospectively enrolled in this study. The S100A9+CD163- cell percentages in classical monocytes showed a pronounced decrease on monocytes in iNSIP compared to that in IPF. In contrast, the percentages of S100A9-CD163+ cells were significantly higher in iNSIP patients than in IPF patients and healthy volunteers. In IPF patients, there was a trend toward a correlation between the percentage of S100A9+CD163- monocytes and the surfactant protein-D (SP-D) serum levels (r = 0.4158, [95% confidence interval (CI) - 0.02042-0.7191], p = 0.051). The individual percentages of S100A9+CD163- and S100A9-CD163+ cells were also independently associated with IPF through multivariate regression analysis. The unadjusted area under the receiver operating characteristic curve (ROC-AUC) to discriminate IPF from iNSIP was (ROC-AUC 0.802, 95% CI [0.687-0.928]), suggesting that these are better biomarkers than serum SP-D (p < 0.05). This preliminary study reports the first comparative characterization of monocyte phenotypes between IPF and iNSIP.

Markers of T Cell Exhaustion and Senescence and Their Relationship to Plasma TGF-ß Levels in Treated HIV+ Immune Non-responders.

Background: Immune non-responders (INR) are HIV+, ART-controlled (>2 yrs) people who fail to reconstitute their CD4 T cell numbers. Systemic inflammation and markers of T cell senescence and exhaustion are observed in INR. This study aims to investigate T cell senescence and exhaustion and their possible association with soluble immune mediators and to understand the immune profile of HIV-infected INR. Selected participants were <50 years old to control for the confounder of older age. Methods: Plasma levels of IL-6, IP10, sCD14, sCD163, and TGF-ß and markers of T cell exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were measured in ART-treated, HIV+ participants grouped by CD4 T cell counts (n = 63). Immune parameters were also measured in HIV-uninfected, age distribution-matched controls (HC; n = 30). Associations between T cell markers of exhaustion and senescence and plasma levels of immune mediators were examined by Spearman rank order statistics. Results: Proportions of CD4 T cell subsets expressing markers of exhaustion (PD-1, TIGIT) and senescence (CD57, KLRG-1) were elevated in HIV+ participants. When comparing proportions between INR and IR, INR had higher proportions of CD4 memory PD-1+, EM CD57+, TEM TIGIT+ and CD8 EM and TEM TIGIT+ cells. Plasma levels of IL-6, IP10, and sCD14 were elevated during HIV infection. IP10 was higher in INR. Plasma TGF-ß levels and CD4 cycling proportions of T regulatory cells were lower in INR. Proportions of CD4 T cells expressing TIGIT, PD-1, and CD57 positively correlated with plasma levels of IL-6. Plasma levels of TGF-ß negatively correlated with proportions of TIGIT+ and PD-1+ T cell subsets. Conclusions: INR have lower levels of TGF-ß and decreased proportions of cycling CD4 T regulatory cells and may have difficulty controlling inflammation. IP10 is elevated in INR and is linked to higher proportions of T cell exhaustion and senescence seen in INR.

Effects of irbesartan on phenotypic alterations in monocytes and the inflammatory status of hypertensive patients with left ventricular hypertrophy.

BACKGROUND: Circulating monocytes and tissue macrophages play complex roles in the pathogenesis of hypertension and the resulting target organ damage. In this study, we observed alterations in the monocyte phenotype and inflammatory state of hypertensive patients with left ventricular hypertrophy (LVH) and studied the effects of irbesartan in these patients. This study might reveal a novel mechanism by which irbesartan alleviates LVH, and it could provide new targets for the prevention and treatment of hypertensive target organ damage. METHODS: CD163 and CD206 expression on monocytes and IL-10 and TNF-α levels in the serum of hypertensive patients with or without LVH and of healthy volunteers were detected. Furthermore, we treated monocytes from the LVH group with different concentrations of irbesartan, and then, CD163, CD206, IL-10 and TNF-α expression was detected. RESULTS: We found, for the first time, that the expression of CD163, CD206 and IL-10 in the LVH group was lower than that in the non-LVH group and healthy control group, but the TNF-α level in the LVH group was significantly higher. Irbesartan upregulated the expression of CD163 and CD206 in hypertensive patients with LVH in a concentration-dependent manner. Irbesartan also increased the expression of IL-10 and inhibited the expression of TNF-α in monocyte culture supernatants in a concentration-dependent manner. CONCLUSIONS: Our data suggest that inflammation was activated in hypertensive patients with LVH and that the monocyte phenotype was mainly proinflammatory. The expression of proinflammatory factors increased while the expression of anti-inflammatory factors decreased. Irbesartan could alter the monocyte phenotype and inflammatory status in hypertensive patients with LVH. This previously unknown mechanism may explain how irbesartan alleviates LVH. Trail registration The study protocols were approved by the Ethical Committee of the Second Affiliated Hospital of Dalian Medical University. Each patient signed the informed consent form.