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1.
Vitamin D Status Modulates Inflammatory Response in HIV+ Subjects: Evidence for Involvement of Autophagy and TG2 Expression in PBMC.
Currò, M, Visalli, G, Pellicanò, GF, Ferlazzo, N, Costanzo, MG, D'Andrea, F, Caccamo, D, Nunnari, G, Ientile, R
International journal of molecular sciences. 2020;(20)
Abstract
Conflicting results on the involvement of vitamin D deficiency in inflammatory and immune response in HIV+ subjects are reported. We aimed to characterize the possible influence of vitamin D status on changes in expression of tissue transglutaminase gene (TGM2) and other genes involved in inflammatory response and autophagy in peripheral blood mononuclear cells (PBMC) from HIV+ subjects. HIV+ subjects (n = 57) under antiretroviral therapy (ART) and healthy controls (n = 40) were enrolled. mRNA levels of 1-alpha-hydroxylase (CYP27B1), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), TGM2, microtubule-associated protein 1A/1B-light chain 3 (LC3), autophagy-related 5 homolog (ATG5), and Beclin 1 (BECN1) were quantified by real-time PCR. In HIV+ subjects, 25(OH)D3 plasma levels were negatively correlated with time since HIV diagnosis. In PBMC from HIV+ subjects, increases in gene expression of TNF-α and IFN-γ in comparison to controls were observed. The highest increase in TNF-α transcripts was observed in HIV+ subjects with deficient 25(OH)D3 levels. Autophagy-related genes LC3, ATG5, and BECN1 were down-regulated in HIV+ subjects. Moreover, TGM2 transcripts were up-regulated in PBMC from HIV+ subjects with 25(OH)D3 deficiency. Changes observed in PBMC from HIV+ subjects appeared to be dependent on vitamin D status. The present results suggest that vitamin D deficiency is associated with changes in the expression of markers of inflammation and autophagy, resulting in immune cell dysfunction.
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2.
Exercise-associated prevention of adult cardiovascular disease in children and adolescents: monocytes, molecular mechanisms, and a call for discovery.
Cooper, DM, Radom-Aizik, S
Pediatric research. 2020;(2):309-318
Abstract
Atherosclerosis originates in childhood and adolescence. The goal of this review is to highlight how exercise and physical activity during childhood and adolescence, critical periods of growth and development, can prevent adult cardiovascular disease (CVD), particularly through molecular mechanisms of monocytes, a key cell of the innate immune system. Monocytes are heterogeneous and pluripotential cells that can, paradoxically, play a role in both the instigation and prevention of atherosclerosis. Recent discoveries in young adults reveal that brief exercise affects monocyte gene pathways promoting a cell phenotype that patrols the vascular system and repairs injuries. Concurrently, exercise inhibits pro-inflammatory monocytes, cells that contribute to vascular damage and plaque formation. Because CVD is typically asymptomatic in youth, minimally invasive techniques must be honed to study the subtle anatomic and physiologic evidence of vascular dysfunction. Exercise gas exchange and heart rate measures can be combined with ultrasound assessments of vascular anatomy and reactivity, and near-infrared spectroscopy to quantify impaired O2 transport that is often hidden at rest. Combined with functional, transcriptomic, and epigenetic monocyte expression and measures of monocyte-endothelium interaction, molecular mechanisms of early CVD can be formulated, and then translated into effective physical activity-based strategies in youth to prevent adult-onset CVD.
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3.
Monocyte and T Cell Immune Phenotypic Profiles Associated With Age Advancement Differ Between People With HIV, Lifestyle-Comparable Controls and Blood Donors.
De Francesco, D, Sabin, CA, Reiss, P, Kootstra, NA
Frontiers in immunology. 2020;:581616
Abstract
MOTIVATION People with HIV on successful antiretroviral therapy show signs of premature aging and are reported to have higher rates of age-associated comorbidities. HIV-associated immune dysfunction and inflammation have been suggested to contribute to this age advancement and increased risk of comorbidities. METHOD Partial least squares regression (PLSR) was used to explore associations between biological age advancement and immunological changes in the T cell and monocyte compartment in people with HIV (n=40), comparable HIV-negative individuals (n=40) participating in the Comorbidity in Relation to AIDS (COBRA) cohort, and blood donors (n=35). RESULTS We observed that age advancement in all three groups combined was associated with a monocyte immune phenotypic profile related to inflammation and a T cell immune phenotypic associated with immune senescence and chronic antigen exposure. Interestingly, a unique monocyte and T cell immune phenotypic profile predictive for age advancement was found within each group. An inflammatory monocyte immune phenotypic profile associated with age advancement in HIV-negative individuals, while the monocyte profile in blood donors and people with HIV was more reflective of loss of function. The T cell immune phenotypic profile in blood donors was related to loss of T cell function, whereas the same set of markers were related to chronic antigen stimulation and immune senescence in HIV-negative individuals. In people with HIV, age advancement was related to changes in the CD4+ T cell compartment and more reflective of immune recovery after cART treatment. IMPACT The identified monocyte and T cell immune phenotypic profiles that were associated with age advancement, were strongly related to inflammation, chronic antigen exposure and immune senescence. While the monocyte and T cell immune phenotypic profile within the HIV-negative individuals reflected those observed in the combined three groups, a distinct profile related to immune dysfunction, was observed within blood donors and people with HIV. These data suggest that varying exposures to lifestyle and infection-related factors may be associated with specific changes in the innate and adaptive immune system, that all contribute to age advancement.
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4.
Altered monocyte phenotype and dysregulated innate cytokine responses among people living with HIV and opioid-use disorder.
Underwood, ML, Nguyen, T, Uebelhoer, LS, Kunkel, LE, Korthuis, PT, Lancioni, CL
AIDS (London, England). 2020;(2):177-188
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Abstract
BACKGROUND Opioid-use disorders (OUD) and hepatitis C or B co-infection (HEP) are common among people living with HIV (PLHIV). The impact of OUD on innate and adaptive immunity among PLHIV with and without HEP is unknown. OBJECTIVES To investigate the impact of OUD on monocyte and T-cell phenotypes, cytokine responses to lipopolysaccharide (LPS) and phytohemagglutinin (PHA), and plasma inflammatory markers, among PLHIV with and without HEP. METHODS Cross-sectional study enrolling PLHIV receiving ART, with and without OUD. Flow cytometry determined monocyte and T-cell phenotypes; LPS and PHA-induced cytokine production was assessed following LPS and PHA stimulation by multiplex cytokine array; plasma IL-6, soluble CD163, and soluble CD14 were measured by ELISA. RESULTS Twenty-two PLHIV with OUD and 37 PLHIV without OUD were included. PLHIV with OUD exhibited higher frequencies of intermediate (CD14CD16) and nonclassical (CD14CD16) monocytes when compared with PLHIV without OUD (P = 0.0025; P = 0.0001, respectively), regardless of HEP co-infection. Soluble CD163 and monocyte cell surface CD163 expression was increased among PLHIV with OUD and HEP, specifically. Regardless of HEP co-infection, PLHIV with OUD exhibited reduced production of IL-10, IL-8, IL-6, IL-1alpha, and TNF-alpha in response to LPS when compared with PLHIV without OUD; PHA-induced production of IL-10, IL-1alpha, IL-1beta, IL-6, and TNF-alpha were also reduced among individuals with OUD. CONCLUSION OUD among PLHIV are associated with altered monocyte phenotypes and a dysregulated innate cytokine response. Defining underlying mechanisms of opioid-associated innate immune dysregulation among PLHIV should be prioritized to identify optimal OUD treatment strategies.
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Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides.
Neidhart, M, Pajak, A, Laskari, K, Riksen, NP, Joosten, LAB, Netea, MG, Lutgens, E, Stroes, ESG, Ciurea, A, Distler, O, et al
Frontiers in immunology. 2019;:791
Abstract
Objectives: Most DAMPs in inflammatory diseases are TLR2- and TLR4-ligands and according to the current concept, repeated stimuli would result in tolerance. Aims of the study were to verify this assumption, to investigate whether epigenetic effectors are involved and to explore the situation in rheumatoid arthritis (RA). Methods: A trained immunity (TI) and tolerance protocol was established using peripheral blood monocytes from healthy donors, β-glucan and lipopolysaccharide (LPS). The training or tolerance capacities of RA-relevant DAMPs were tested. Results: β-Glucan-, oS100A4-, HMBG1-, and HSP90-pretreated monocytes showed increased IL-6 responses to LPS re-stimulation. β-Glucan, oS100A and tenascin C induced training of monocytes to release more TNFα. In comparison to β-glucan, most DAMPs tested induced less TI, with exception of oS100A4. Monocytes exposed to oS100A4 showed increased IL-1β, IL-6, and TNFα in response to LPS, in spite that both stimulate TLR4. RNASEq upon β-glucan or oS100A4 revealed similar changes in chemokines/cytokines and epigenetic effectors; 17 epigenetic effectors correlated with chemokine/cytokine gene expression; PRDM8 was associated with more chemokine and cytokine transcripts. Knockdown of PRDM8 abolished TI induced by oS100A4. In RA, plasma S100A4 correlated with increased CSF2, and increased PRDM8 transcription in RA monocytes was associated with increased plasma CCL5 and IL-6, as well as therapy-resistance. Conclusion: Bypass of tolerance by DAMPs might be a phenomenon as important as TI, since it could explain how chronic inflammation can be maintained in spite of an environment with multiple TLR2/TLR4-ligands. In RA monocytes, a PRDM8-dependent TI mechanism could be responsible for sustained chemokine/cytokines levels.
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Incorporation of dynamic segmented neutrophil-to-monocyte ratio with leukocyte count for sepsis risk stratification.
Fang, WF, Chen, YM, Wang, YH, Huang, CH, Hung, KY, Fang, YT, Chang, YC, Lin, CY, Chang, YT, Chen, HC, et al
Scientific reports. 2019;(1):19756
Abstract
The association between sepsis and segmented neutrophil-to-monocyte (SeMo) ratio is unclear. We postulated that an increase in dynamic SeMo ratio measurement can be applied in risk stratification. This retrospective study included 727 consecutive sepsis patients in medical intensive care units (ICUs), including a subpopulation of 153 patients. According to the leukocyte (white blood cell, WBC) count on day 3 (normal range, between 4,000/µL and 12,000/µL) and delta SeMo (value of SeMo ratio on day 3 minus value of SeMo ratio on day 1; normal delta SeMo, <7), patients were grouped into 3 (delta SeMo & WBC tool). The survival lines separated significantly with hazard ratios of 1.854 (1.342-2.560) for the delta SeMo or WBC abnormal group and 2.860 (1.849-4.439) for the delta SeMo and WBC abnormal group compared to the delta SeMo and WBC normal group. Delta SeMo & WBC tool and delta sequential organ failure assessment (SOFA) tool performed better than the other tools (delta SeMo, delta WBC, day 3 WBC, and day 1 WBC). Severity in delta SeMo & WBC tool and delta SeMo tool reflected the immune dysfunction score, cytokine expression, and human leukocyte antigen D-related monocyte expression on day 1 and day 3. There was correspondence between delta SOFA and delta WBC and between delta SeMo and delta cytokine expression. Incorporation of dynamic SeMo ratio with WBC count provides risk stratification for sepsis patients admitted in the ICU.
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Classical monocytes from older adults maintain capacity for metabolic compensation during glucose deprivation and lipopolysaccharide stimulation.
Yarbro, JR, Pence, BD
Mechanisms of ageing and development. 2019;:111146
Abstract
Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that classical monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism along with impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose deprivation as measured on a Seahorse XFp system. Additionally, aged classical monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged classical monocytes maintain effector and metabolic functions during glucose deprivation, at least in an ex vivo context.
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NF-κB-Dependent Production of ROS and Restriction of HSV-1 Infection in U937 Monocytic Cells.
Marino-Merlo, F, Papaianni, E, Frezza, C, Pedatella, S, De Nisco, M, Macchi, B, Grelli, S, Mastino, A
Viruses. 2019;(5)
Abstract
Herpes simplex virus 1 (HSV-1) can infect a wide range of cell types, including cells of the adaptive and innate immunity but, normally, it completes a fully-permissive replication cycle only in epithelial or neural cells. Complex mechanisms controlling this delicate balance in immune cells and consequent restriction of HSV-1 infection in these cells have not been completely elucidated. We have recently demonstrated that the transcription factor nuclear factor kappa B (NF-κB) can act as a main permissiveness regulator of HSV-1 infection in monocytic cells, however, mediators involved in this regulation have not been identified. To better define mechanisms involved in this phenomenon and, particularly, the possible involvement of ROS, wild type U937 cells or U937 cells stably transfected with a dominant-negative (DN) IκB-mutant and selenium-containing compounds, as anti-oxidants, were utilized. The main results can be summarized as follows. HSV-1 infection induces an immediate ROS production in U937 monocytic cells that can efficiently activate NF-κB but not in DN-IκB-mutant cells. Treatment with selenium-containing antioxidants efficiently inhibited HSV-1-induced ROS generation while producing increased levels of HSV-1 replication and a reduction of HSV-1-induced NF-κB activation in U937 monocytic cells. Our results suggest a scenario in which an efficient NF-κB-dependent ROS production in response to infection could contribute in limiting HSV-1 replication in monocytes/macrophages, thus avoiding possible irreparable damage to the innate immune system of the host during HSV-1 infection.
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Secretion of IL-1β From Monocytes in Gout Is Redox Independent.
Alberts, BM, Bruce, C, Basnayake, K, Ghezzi, P, Davies, KA, Mullen, LM
Frontiers in immunology. 2019;:70
Abstract
The pro-inflammatory cytokine interleukin-1β (IL-1β) plays important roles in immunity but is also implicated in autoimmune disease. The most well-established mechanism of IL-1β secretion is via activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome which requires an initial priming signal followed by an activating signal. However, the precise mechanism by which the inflammasome is activated remains unclear. The role of reactive oxygen species (ROS) in this process is contradictory, with some studies suggesting that ROS are crucial while others describe opposite effects. In this study, we evaluated the effects of oxidative stress on IL-1β secretion. Gout is a disease driven solely by IL-1β secretion in response to monosodium urate (MSU) crystals which form during periods of hyperuricemia and thus presents an opportunity to study factors contributing to IL-1β secretion. Sera and monocytes were isolated from patients with gout to determine whether differences in antioxidant status could explain the susceptibility of these individuals to gout attacks. In addition, sera and monocytes were collected from patients with chronic kidney disease (CKD) for comparison as this condition is associated with high levels of oxidative stress and disturbances in serum uric acid levels. There were differences in some aspects of antioxidant defenses in gout patients and these were mainly due to higher serum uric acid. Monocytes from gout patients were more responsive to priming, but not activation, of the NLRP3 inflammasome. However, expression of the components of the NLRP3 inflammasome were unaffected by priming or activation of the inflammasome, nor were these expression levels differentially regulated in gout patients. Inhibition of ROS by N-Acetyl Cysteine inhibited TLR2-induced priming of the NLRP3 inflammasome, but had no effect on MSU-induced activation. Together these findings demonstrate that oxidative stress only affects priming of the NLRP3 inflammasome but does not influence activation.
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Human monocyte transcriptional profiling identifies IL-18 receptor accessory protein and lactoferrin as novel immune targets in hypertension.
Alexander, MR, Norlander, AE, Elijovich, F, Atreya, RV, Gaye, A, Gnecco, JS, Laffer, CL, Galindo, CL, Madhur, MS
British journal of pharmacology. 2019;(12):2015-2027
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Abstract
BACKGROUND AND PURPOSE Monocytes play a critical role in hypertension. The purpose of our study was to use an unbiased approach to determine whether hypertensive individuals on conventional therapy exhibit an altered monocyte gene expression profile and to perform validation studies of selected genes to identify novel therapeutic targets for hypertension. EXPERIMENTAL APPROACH Next generation RNA sequencing identified differentially expressed genes in a small discovery cohort of normotensive and hypertensive individuals. Several of these genes were further investigated for association with hypertension in multiple validation cohorts using qRT-PCR, regression analysis, phenome-wide association study and case-control analysis of a missense polymorphism. KEY RESULTS We identified 60 genes that were significantly differentially expressed in hypertensive monocytes, many of which are related to IL-1β. Uni- and multivariate regression analyses of the expression of these genes with mean arterial pressure (MAP) revealed four genes that significantly correlated with MAP in normotensive and/or hypertensive individuals. Of these, lactoferrin (LTF), peptidoglycan recognition protein 1 and IL-18 receptor accessory protein (IL18RAP) remained significantly elevated in peripheral monocytes of hypertensive individuals in a separate validation cohort. Interestingly, IL18RAP expression associated with MAP in a cohort of African Americans. Furthermore, homozygosity for a missense single nucleotide polymorphism in LTF that decreases antimicrobial function and increases protein levels (rs1126478) was over-represented in patients with hypertension relative to controls (odds ratio 1.16). CONCLUSIONS AND IMPLICATIONS These data demonstrate that monocytes exhibit enhanced pro-inflammatory gene expression in hypertensive individuals and identify IL18RAP and LTF as potential novel mediators of human hypertension. LINKED ARTICLES This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.