Abstract 132: Monocytes Activation by Salt is Associated With Cardiovascular Risk Factors

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Natalia Ruggeri Barbaro ◽  
Jason D Foss ◽  
Roxana Loperena ◽  
Fernando Elijovich ◽  
Cheryl L Laffer ◽  
...  
Keyword(s):  
Risk Factors ◽  
Pulse Pressure ◽  
Salt Intake ◽  
Inflammatory Cells ◽  
Surface Expression ◽  
High Salt ◽  
Human Monocytes ◽  
Tnf Α ◽  
Inflammatory Phenotype ◽  
Underlying Risk Factor

Several studies have established a relationship between hypertension and salt intake; however the mechanisms by which salt causes hypertension are poorly understood. There is also evidence that sodium (Na+) accumulates in the interstitium with aging and hypertension in concentrations exceeding the plasma. We tested the hypothesis that increased NaCl would convert human monocytes to an inflammatory phenotype and to define mechanisms involved. We exposed monocytes from 17 human volunteers to normal physiological NaCl (NS: 150 mM/L), elevated NaCl (HS: 190 mM/L), or an equiosmoloar concentration of mannitol. Exposure of human monocytes to high salt, but not mannitol, increased formation of immunogenic isolevuglandins (isoLG) (NS: 1688±384 vs Mann:1762±429 vs HS: 2381± 635 MFI p<0.002). This was associated with an increase in the dendritic cell (DC) marker CD83 (NS: 503±81 vs Mann: 530± 106 vs HS: 764 ± 136 MFI p<0.001). Exposure to high salt also stimulated production of IL-6 (NS: 2145±771, Mann: 1122±295 and HS: 5187±1146 pg/mL, p=0.04), IL-β (NS: 94±35, Mann: 62±16 and HS: 224±98 pg/mL, p=0.01) and TNF-α (NS:1.9±0.3, Mann: 3.42±1.4 and HS: 4.4±2.1, p<0.0001). In additional experiments, we found that prolonged (7 day) exposure to high salt increased surface expression of CD209, another DC marker (NS: 22±9 vs HS: 34 ± 14, p=0.001) and promoted conversion of the cells to a DC morphology. The propensity for monocytes to respond to NaCl was influence by the patient’s risk factors. The increase in IsoLG (HS-NS) correlated with pulse pressure (mmHg, r=0.51, <0.04), BMI (Kg/m2, r=0.66, p=0.005), total cholesterol (mg/dL, r=0.55, p<0.05) and glucose (mg/dL, r=0.72, p=0.003). Stepwise multivariate regression revealed that BMI and pulse pressure are independent predictors of IsoLG formation in response to salt. These findings suggest that high extracellular NaCl promotes differentiation and activation of monocytes and that these pleotropic inflammatory cells exhibit a previously undefined salt sensitivity corresponding to patients’ underlying risk factor profile.

Cardiac sympathetic afferent stimulation induces salt-sensitive sympathoexcitation through hypothalamic epithelial Na+ channel activation

2015 ◽  
Vol 308 (5) ◽  
pp. H530-H539 ◽  
Author(s):  
Koji Ito ◽  
Yoshitaka Hirooka ◽  
Kenji Sunagawa
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Salt Intake ◽  
Receptor Activation ◽  
High Salt ◽  
Salt Diet ◽  
Intracerebroventricular Infusion ◽  
High Salt Intake ◽  
Tnf Α ◽  
Excitatory Responses

The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na+ channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na+, we performed an intracerebroventricular infusion of high Na+-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity.

P6221Salt consumption as a predictor of cardiovascular events among hypertensive patients: a 5-year follow-up study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Kasiakogias ◽  
C Tsioufis ◽  
D Konstantinidis ◽  
I Leontsinis ◽  
P Iliakis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Cardiovascular Events ◽  
Salt Intake ◽  
Cardiovascular Morbidity ◽  
High Salt ◽  
Hypertensive Patients ◽  
Cox Regression Analysis ◽  
Salt Consumption

Abstract Background/Introduction Salt intake is linked to hypertension but data on its association with incident cardiovascular events, especially among hypertensives, is limited. Purpose To examine the prospective association of different salt consumption levels with cardiovascular morbidity in a hypertensive population. Methods We followed 2130 hypertensive patients (age 57±12 years, 11.2% untreated) without a history of cardiovascular disease for a mean period of 5.3±3.3 years. At the baseline examination, salt intake was evaluated by a structured validated questionnaire. Accordingly, the study population was divided into three groups: hypertensives with a low (1079 patients, 51% of the population), a moderate (895 patients, 42%) and a high salt consumption (146 patients, 7%). During follow-up, patients underwent clinic visits at least yearly for management of hypertension and risk factors. The outcome studied was the composite of non-fatal cardiovascular events. Results The composite endpoint (19 strokes and 65 cases of coronary artery disease) occurred in 84 patients (3.9%). At baseline, increasing salt consumption was significantly associated with age, body mass index, office blood pressure and renal function. Unadjusted Cox regression analysis showed that, compared to the reference group, the risk for cardiovascular morbidity was similar in patients with moderate salt consumption (HR: 1.1, 95% CI: 0.71–1.77) but significantly higher in patients with high salt consumption (HR: 2.12, 95% CI: 1.09–4.38). This pattern was clearly sustained after adjusting for multiple risk factors including baseline blood pressure levels. Conclusions Among hypertensive patients, heavy salt consumption is associated with an increased cardiovascular risk, while moderate consumption does not affect patient outcome.

Abstract 091: High Salt Promotes Conversion of Human Monocytes Into Dendritic Cells via Formation of Immunogenic Isoketals

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Natalia R Barbaro ◽  
Jason D Foss ◽  
Kim R Montaniel ◽  
Wei Chen ◽  
David G Harrison ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Salt Intake ◽  
Fold Increase ◽  
High Salt ◽  
Human Monocytes ◽  
Gm Csf ◽  
High Salt Intake ◽  
Inflammatory State ◽  
Modified Proteins ◽  
Antigen Presenting

High salt intake and inflammation are implicated in the genesis of hypertension. Recently it has become clear that sodium can accumulate in the interstitial space in concentrations exceeding that of the plasma, and that these high salt (HS) concentrations can be pro-inflammatory. Our laboratory recently published a new pathway in which increased oxidative stress in dendritic cells (DCs) leads to formation of isoketal-modified proteins which act as neo-antigens to activate T cells. We hypothesized that increasing sodium chloride (NaCl) in excess activates antigen presenting cells via formation of immunogenic isoketals. We exposed monocytes from human volunteers to normal physiological NaCl (NS: 150 mM/L), elevated NaCl concentrations (HS: 190 mM/L), or an equiosmoloar concentration of mannitol. We found that exposure of human monocytes to high salt, but not mannitol, caused a 2-fold increase in formation of isoketal-modified proteins. This was associated with an increase in activation marker CD86 (NS: 466 ± 192 vs HS: 596 ± 324 MFI p<0.05) and production of inflammatory cytokines IL-6, IL-β and TNF-α. Interestingly, these cells expressed surface markers indicative of transformation to DCs, as evidenced by their acquisition of surface marker CD83. In additional immunofluorescence studies, we found that monocytes exposed to HS for 7 days acquire a DC like morphology. Moreover, using flow cytometry, we confirmed that high salt exposure causes these cells to lose the monocyte marker CD14 (NS: 41.1 ± 15.4 vs HS: 19.9 ± 6.4 MFI; p<0.05), and gain the DC marker CD209 (NS: 24.2 ± 1.0 vs HS: 49.3 ± 0.7 MFI; p<0.001). None to these effects were mimicked by mannitol and scavenging of isoketals during high salt exposure. High salt dramatically increased mRNA expression of GM-CSF (NS: 758 ± 440.8 vs HS: 5476 ± 2268 MFI; p<0.05), IL-4 NS: 1868 ± 560.6 vs HS: 4867 ± 1152 MFI; p<0.05) and Flt3 (NS: 2526 ± 636.8 vs HS: 10014 ± 2370 MFI; p<0.05), which are known to mediate monocyte conversion to DCs. Thus, we have defined a novel pathway whereby high NaCl concentrations lead to transformation of monocytes to DCs due to increased formation of immunogenic isoketals. These observations provide insight into how elevated sodium environments lead to an inflammatory state.

scholarly journals Sodium activates human monocytes via the NADPH oxidase and isolevuglandin formation

2020 ◽  
Author(s):  
Natalia Ruggeri Barbaro ◽  
Justin Van Beusecum ◽  
Liang Xiao ◽  
Luciana do Carmo ◽  
Ashley Pitzer ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cells ◽  
Nadph Oxidase ◽  
Immune Cells ◽  
Adduct Formation ◽  
High Salt ◽  
Human Monocytes ◽  
Activation Markers

Abstract Aims Prior studies have focused on the role of the kidney and vasculature in salt-induced modulation of blood pressure; however, recent data indicate that sodium accumulates in tissues and can activate immune cells. We sought to examine mechanisms by which salt causes activation of human monocytes both in vivo and in vitro. Methods and results To study the effect of salt in human monocytes, monocytes were isolated from volunteers to perform several in vitro experiments. Exposure of human monocytes to elevated Na+ex vivo caused a co-ordinated response involving isolevuglandin (IsoLG)-adduct formation, acquisition of a dendritic cell (DC)-like morphology, expression of activation markers CD83 and CD16, and increased production of pro-inflammatory cytokines tumour necrosis factor-α, interleukin (IL)-6, and IL-1β. High salt also caused a marked change in monocyte gene expression as detected by RNA sequencing and enhanced monocyte migration to the chemokine CC motif chemokine ligand 5. NADPH-oxidase inhibition attenuated monocyte activation and IsoLG-adduct formation. The increase in IsoLG-adducts correlated with risk factors including body mass index, pulse pressure. Monocytes exposed to high salt stimulated IL-17A production from autologous CD4+ and CD8+ T cells. In addition, to evaluate the effect of salt in vivo, monocytes and T cells isolated from humans were adoptively transferred to immunodeficient NSG mice. Salt feeding of humanized mice caused monocyte-dependent activation of human T cells reflected by proliferation and accumulation of T cells in the bone marrow. Moreover, we performed a cross-sectional study in 70 prehypertensive subjects. Blood was collected for flow cytometric analysis and 23Na magnetic resonance imaging was performed for tissue sodium measurements. Monocytes from humans with high skin Na+ exhibited increased IsoLG-adduct accumulation and CD83 expression. Conclusion Human monocytes exhibit co-ordinated increases in parameters of activation, conversion to a DC-like phenotype and ability to activate T cells upon both in vitro and in vivo sodium exposure. The ability of monocytes to be activated by sodium is related to in vivo cardiovascular disease risk factors. We therefore propose that in addition to the kidney and vasculature, immune cells like monocytes convey salt-induced cardiovascular risk in humans.

P1.10 PULSE PRESSURE IN RELATION TO 24-HOUR URINARY SODIUM EXCRETION IN A SAMPLE OF HIGH-SALT INTAKE POPULATION

2015 ◽  
Vol 12 (C) ◽  
pp. 5
Author(s):  
Adam Bednarski* ◽  
Katarzyna Stolarz-Skrzypek ◽  
Grzegorz Kielbasa ◽  
Agata Franczyk ◽  
Malgorzata Kloch-Badelek ◽  
...  
Keyword(s):  
Pulse Pressure ◽  
Sodium Excretion ◽  
Salt Intake ◽  
Urinary Sodium Excretion ◽  
Urinary Sodium ◽  
High Salt ◽  
High Salt Intake

Survival and factors associated with cardiovascular mortality in rural area of Russia. Results of a 7-year prospective study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Myrzamatova ◽  
A Kontsevaya ◽  
A Kashirin ◽  
M Sirotko ◽  
M Khudyakov
Keyword(s):  
Physical Activity ◽  
Risk Factors ◽  
Cardiovascular Mortality ◽  
Rural Areas ◽  
Salt Intake ◽  
High Salt ◽  
Noncommunicable Diseases ◽  
Processed Meat ◽  
Meat Intake ◽  
High Salt Intake

Abstract Introduction In Russia, mortality rates from CVD are one of the highest in the world. In recent decades, it has been demonstrated that the contribution of a modifying risk factors to cardiovascular mortality in different populations can vary significantly. Aim To evaluate the 7-year survival and association of risk factors with cardiovascular mortality among rural residents of Russia. Materials and methods This study was carried out as part of the international project InterEpid, which included a one-stage epidemiological study of the prevalence of major chronic noncommunicable diseases and their risk factors (n=1050), and a prospective stage among residents of rural areas of Russia. The analysis includes the results of a survey of representative samples of the rural population of the Samara Region of Russian Federation (n=919) aged 20–64, response rate 87,5%.The following endpoints are included in the analysis: 1. Cases of death from all causes; 2. Deaths from CVD. Results In Samara region 7-year survival was 92.7%. Cardiovascular diseases were most frequent cause of deaths (42%). Cardiovascular mortality was significantly associated with hypertension RR 2.11 (1.32; 2.94), p=0.004, low physical activity RR 1.82 (1.02; 2.41), p=0.009, high salt intake RR 1.28 (0.84; 2.21), p=0.03 and high processed meat intake RR 1.37 (0.91; 1.93), p=0.03. Smoking had a significant effect on cardiovascular mortality only among men RR 2.11 (1.14; 2.84), p=0.005. Conclusion 7-year follow up demonstrated significant unfavorable effect of smoking on men's cardiovascular mortality; hypertension, low physical activity, high salt and processed meat intake on the risk of cardiovascular mortality in both sexes in rural areas of Russia. All this underlines the need to develop differentiated preventive and treatment and preventive programs adjusted to country specific of risk factors prevalence and its impact on the prognosis. 7-year survival (Samara region) Funding Acknowledgement Type of funding source: None

scholarly journals The prevalence and habit-associated risk factors of gastroesophageal reflux disease among fishermen in Indonesia

2022 ◽  
Vol 22 (3) ◽  
pp. 174-179
Author(s):  
Ahmad Fariz Malvi Zamzam Zein ◽  
Catur Setiya Sulistiyana ◽  
Tissa Octavira Permatasari ◽  
Uswatun Khasanah ◽  
Tiar Masykuroh Pratamawati ◽  
...  
Keyword(s):  
Risk Factors ◽  
Gastroesophageal Reflux Disease ◽  
Gastroesophageal Reflux ◽  
Hand Hygiene ◽  
Reflux Disease ◽  
Salt Intake ◽  
High Salt ◽  
Bivariate Analysis ◽  
High Salt Intake ◽  
Associated Risk Factors

Background. This study was aimed to investigate the prevalence and habit-associated risk factors of gastroesophageal reflux disease (GERD) among fishermen.Methods. A cross-sectional study was conducted among 168 adult fishermen in Cirebon Regency, West Java, Indonesia. A self-administered questionnaire was given. The questionnaire consisted of demographic characteristics and validated GERD questionnaire (GERDQ) in Indonesian language. Data were analyzed using descriptive statistics and chi-square test. The study has been approved by the Medical Research Ethic Comiittee.Results. The medan age of the participants was 39.0 (24-86) years old. They were predominanty (60.7%) female. The prevalence of GERD was 22.6%. According to bivariate analysis, there was association between smoking (PR 1.181; 95%CI 1.013-1.377;p 0.041), high-salt intake (PR 2.419;95%CI 1.079-5.424; p 0.029), herb consumption (PR 3.068; 95%CI 1.307-7.200; p 0.008), poor hand hygiene (PR 3.202; 95%ci 1.445-7.095; p 0.003), and non-steroidal anti-inflammatory drug (NSAID) consumption (PR 3.062; 95%CI 1.446-6.488; p 0.00) with GERD. Tea consumption, coffee consumption, and raw vegetable eating were not associated with GERD.Conclusions This population-based study showed that the prevalence of GERD among fishermen in Indonesia is high. Habits associated with GERD in this study were smoking, high-salt intake, herb consumption poor, hand hygiene,

scholarly journals The Impact of the PCSK-9 / VLDL-Receptor Axis on Inflammatory Cell Polarization

2021 ◽  
Author(s):  
Maria Luisa Barcena ◽  
Misael Estepa ◽  
Louis Marx ◽  
Anne Breiter ◽  
Natalie Haritonow ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Macrophage Polarization ◽  
Inflammatory Cells ◽  
Cell Polarization ◽  
Pcsk9 Inhibitors ◽  
Tnf Α ◽  
Inflammatory Phenotype ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
The Impact

Abstract Background: Studies have shown that lipoproteins, including LDL, VLDL, and ApoE2 have an impact on macrophage polarization, important to atherosclerosis progression. PCSK9 is a key mediator regulating the expression of lipoprotein receptors. The present study investigates the effect of the VLDL/VLDL-R axis on mononuclear cell polarization, as well as the role of PCSK9 and PCSK9 inhibitors (PCSK9i) within this network.Methods: Human monocytic THP-1 cells and human monocyte-derived macrophages isolated from PBMC were treated with LPS/IFN-γ to induce a pro-inflammatory phenotype or with IL-4 /IL-13 to induce an anti-inflammatory phenotype. Cells were then subjected to further treatments including VLDL, LDL, PCSK9, PCSK9i, anti-LDL-R; PMA and TSP-1.Results: LPS/IFN-γ treatment promoted a pro-inflammatory state with an increased expression of pro-inflammatory mediators e.g., TNF-α, CD80, and IL-1β. VLDL co-treatment induced a switch of this pro-inflammatory phenotype to an anti-inflammatory phenotype. In pro-inflammatory cells, VLDL significantly decreased the expression of the M1-markers e.g., TNF-α, CD80, and IL-1β. These effects were eliminated by PCSK9 and restored by co-incubation with a PCSK9i. Migration assays demonstrated that pro-inflammatory cells displayed a significantly higher invasive capacity compared to untreated cells or anti-inflammatory cells. Moreover, pro-inflammatory cell chemotaxis was significantly decreased by VLDL-mediated acquisition of the anti-inflammatory phenotype. PCSK9 significantly lessened this VLDL-mediated migration inhibition, which was reversed by the PCSK9i.Conclusion: VLDL promotes macrophage differentiation towards the anti-inflammatory phenotype. PCSK9, via its capacity to inhibit VLDL-R expression, reverses the VLDL-mediated anti-inflammatory switch, thereby promoting a pro-inflammatory phenotype. Thus, anti-PCSK9 therapies may exert pro-inflammatory suppression within the vessel wall.

Abstract 383: Hypertensive and Renal Injury Responses to Angiotensin II and High Salt Intake in Mice Lacking the Gene for Interleukin-10

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Purnima Singh ◽  
Alexander Castillo ◽  
Dewan S Majid
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Salt Intake ◽  
Gene Knockout ◽  
Interleukin 10 ◽  
Renal Tissue ◽  
Protective Role ◽  
High Salt ◽  
High Salt Intake ◽  
Tnf Α

Endogenous interleukin-10 (IL-10) exerts immune down-regulating action on the generation of tumor necrosis factor-alpha (TNF-α). The present study examined the hypothesis that IL-10 plays a protective role in hypertension and renal injury induced by angiotensin II (AngII) and high salt (HS) diet by minimizing TNF-α production. Systemic blood pressure (BP; monitored by implanted radio-telemetry), TNF-α level in plasma and in the kidney (by ELISA) as well as renal injury (glomerulosclerosis, GS by PAS staining and renal interstitial fibrosis, RIF by Trichrome staining) responses to chronic infusion of AngII (400 ng/min; osmotic minipump) for 2 wks were evaluated in wild-type (WT; n=11) and IL-10 gene knockout mice (KO; n=11) which were fed either normal (NS; 0.03% NaCl, n=5) or HS (4% NaCl; n=6) diets. On the last day of the experiment, a 24 hr urine collection was made using metabolic cages prior to sacrificing the mice for the collection of plasma and renal tissue samples. The mean baseline BP in KO was lower (104±3 vs 116±4 mmHg) than that in WT. Increase in BP in AngII+HS treated KO was lower (Δ 20±5 vs Δ 39±2 mmHg) than that in WT but similar in AngII+NS treated KO and WT (Δ 40±3 vs Δ 47±7 mmHg). In AngII+HS treated WT, TNF-α was higher in plasma (69±6 vs 34±4 pg/mL) and in renal tissue (208±15 vs 95±11 pg/mg protein) compared to values in WT treated with AngII+NS. In AngII+HS treated KO, TNF-α was lower in plasma (20±3 vs 180±44 pg/mL) and in renal tissue (205±23 vs 277±23 vs pg/mg protein) compared to values in KO treated with AngII+NS. The urinary nitrate/nitrite excretion rate was higher in AngII+NS (0.56±0.25 vs 0.08±0.01 mM/24 hr) and AngII+HS (1.23±0.12 vs 0.18±0.02 mM/24 hr) treated KO compared to the correspondingly treated WT. The eNOS protein expression was higher in KO treated with AngII+NS (~2 folds) or AngII+HS (~3 folds) compared to those in treated WT. GS (24.6±1.3 vs 13.8±2.1 %) and RIF (10.6±1.1 vs 7.8±0.5 %) changes were greater in AngII+NS treated KO than those in treated WT. However, the changes were minimal in HS treated groups. In conclusion, these data demonstrate that there exists an interaction of IL-10 and eNOS activity in the regulation of TNF-α in the kidney that provides a protective role by minimizing hypertension and renal injury induced by Ang II and HS intake.

scholarly journals Origin of Monocytes/Macrophages Contributing to Chronic Inflammation in Chagas Disease: SIRT1 Inhibition of FAK-NFκB-Dependent Proliferation and Proinflammatory Activation of Macrophages

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 80 ◽  
Author(s):  
Xianxiu Wan ◽  
Imran Hussain Chowdhury ◽  
Zuliang Jie ◽  
Subhadip Choudhuri ◽  
Nisha Jain Garg
Keyword(s):  
Transcription Factors ◽  
Chagas Disease ◽  
Chronic Phase ◽  
Surface Expression ◽  
Yolk Sac ◽  
Cytokine Gene Expression ◽  
Hematopoietic Stem ◽  
Tnf Α ◽  
Inflammatory Phenotype ◽  
And Migration

Background: Trypanosoma cruzi (Tc) causes Chagas disease (CD) that is the most frequent cause of heart failure in Latin America. TNF-α+ monocytes/macrophages (Mo/Mφ) are associated with inflammatory pathology in chronic CD. In this study, we determined the progenitor lineage of Mo/Mφ contributing to inflammation and examined the regulatory role of SIRT1 in modulating the Mo/Mφ response in Chagas disease. Methods and Results: C57BL/6 mice were infected with Tc, treated with SIRT1 agonist (SRT1720) after control of acute parasitemia, and monitored during chronic phase (150 days post-infection). Flow cytometry studies showed an increase in maturation of bone marrow hematopoietic stem cell (HSC)-derived Mo of proinflammatory and anti-inflammatory phenotype in acutely- and chronically-infected mice; however, these cells were not increased in splenic compartment of infected mice. Instead, yolk-sac-derived CD11b+ F4/80+ Mo/Mφ were increased in sinusoidal compartment of Chagas mice. The splenic CD11b+ F4/80+ Mo/Mφ of Chagas (vs. control) mice exhibited increased mRNA, protein, and surface expression of markers of proinflammatory phenotype (CD80+/CD64+ > CD200+/CD206+) associated with proinflammatory cytokines response (IL-6+TNF-α >> Arg-1+IL-10), and these were also detected in the myocardium of chronically infected mice. Infected mice treated with SRT1720 (vs. infected/untreated) exhibited decreased splenic expansion and myocardial infiltration of proinflammatory Mo/Mφ. SRT1720 did not alter the inherent capability of splenic Mo/Mφ of Chagas mice to respond to pathogen stimulus. Instead, SRT1720 dampened the Tc-induced increase in the expression and/or phosphorylation of focal adhesion kinase (FAK) and downstream transcription factors (Pu.1, c-Myb, and Runx1) involved in Mφ proliferation and migration and Notch1 involved in functional activation. Studies in cultured Mφ confirmed the agonistic effects of SIRT1 in controlling the Tc-induced, FAK-dependent increase in the expression of transcription factors and showed that SIRT1 agonist and FAK inhibitor abrogated the NF-κB transcriptional activity and inflammatory cytokine gene expression in Tc-infected Mφ. Conclusions: The proinflammatory Mo/Mφ of yolk sac origin drive the splenic and tissue inflammatory response in chronic CD. SRT1720 reprogrammed the Tc-induced FAK-dependent transcription factors involved in Mφ proliferation and proinflammatory activation in Chagas disease.

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