RESUMO
The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.
Assuntos
Interferon gama/imunologia , Interleucina-10/imunologia , SARS-CoV-2/imunologia , Células Th1/imunologia , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , COVID-19/imunologia , COVID-19/patologia , Complemento C3a/imunologia , Complemento C3b/imunologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Ativação Linfocitária/imunologia , Receptores de Calcitriol/metabolismo , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Transcrição Gênica/genéticaRESUMO
BACKGROUND: Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease. METHODS: We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF. RESULTS: TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating ß-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF. CONCLUSIONS: In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans.
Assuntos
Aterosclerose , Modelos Animais de Doenças , Fígado , Camundongos Knockout para ApoE , Receptores de LDL , Animais , Receptores de LDL/genética , Receptores de LDL/deficiência , Aterosclerose/prevenção & controle , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/etiologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fatores de Tempo , Jejum/sangue , Camundongos , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Hipercolesterolemia/complicações , Dieta Aterogênica , Aumento de Peso , Camundongos Knockout , Doenças da Aorta/prevenção & controle , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/metabolismo , Lipídeos/sangue , Apolipoproteínas ERESUMO
BACKGROUND: Air pollution and noise exposures individually associate with major adverse cardiovascular events (MACE) via a mechanism involving arterial inflammation (ArtI); however, their combined impact on ArtI and MACE remains unknown. We tested whether dual (vs. one or neither) exposure associates with greater ArtI and MACE risk and whether MACE risk is mediated via ArtI. METHODS: Individuals (N = 474) without active cancer or known cardiovascular disease with clinical 18F-FDG-PET/CT imaging were followed for 5 years for MACE. ArtI was measured. Average air pollution (particulate matter ≤ 2.5 µm, PM2.5) and transportation noise exposure were determined at individual residences. Higher exposures were defined as noise > 55 dBA (World Health Organization cutoff) and PM2.5 ≥ sample median. RESULTS: At baseline, 46%, 46%, and 8% were exposed to high levels of neither, one, or both pollutants; 39 experienced MACE over a median 4.1 years. Exposure to an increasing number of pollutants associated with higher ArtI (standardized ß [95% CI: .195 [.052, .339], P = .008) and MACE (HR [95% CI]: 2.897 [1.818-4.615], P < .001). In path analysis, ArtI partially mediated the relationship between pollutant exposures and MACE (P < .05). CONCLUSION: Air pollution and transportation noise exposures contribute incrementally to ArtI and MACE. The mechanism linking dual exposure to MACE involves ArtI.
Assuntos
Poluentes Atmosféricos , Doenças Cardiovasculares , Poluentes Ambientais , Ruído dos Transportes , Humanos , Ruído dos Transportes/efeitos adversos , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Material Particulado/análise , Inflamação , Poluentes Ambientais/análiseRESUMO
Patients with psoriasis have a higher prevalence of cardiovascular risk factors. This study evaluated cardiovascular screening practices and statin prescribing habits among dermatologists, rheumatologists and primary care physicians (PCPs) through an online questionnaire, which was distributed through the Spanish scientific societies of the above-mentioned specialties. A total of 299 physicians (103 dermatologists, 94 rheumatologists and 102 PCPs) responded to the questionnaire. Of these, 74.6% reported screening for smoking, 37.8% for hypertension, 80.3% for dyslipidaemia, and 79.6% for diabetes mellitus. Notably, only 28.4% performed global screening, defined as screening for smoking, hypertension, dyslipidaemia, and diabetes mellitus by the same physician, and 24.4% reported calculating 10-year cardiovascular disease (CVD) risk, probably reflecting a lack of comprehensive cardiovascular risk assessment in these patients. This study also identified unmet needs for awareness of cardiovascular comorbidities in psoriasis and corresponding screening and treatment recommendations among PCPs. Of PCPs, 61.2% reported not being aware of the association between psoriasis and CVD and/or not being aware of its screening recommendations, and 67.6% did not consider psoriasis as a risk-enhancing factor when deciding on statin prescription. Thirteen dermatologists (12.6%) and 35 rheumatologists (37.2%) reported prescribing statins. Among those who do not prescribe, 49.7% would be willing to start their prescription.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipertensão , Médicos de Atenção Primária , Psoríase , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Reumatologistas , Dermatologistas , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Psoríase/epidemiologia , Prescrições , Hábitos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controleRESUMO
BACKGROUND: Psoriasis (PSO) is a skin disorder with systemic inflammation and high coronary artery disease risk. A distinct lipid phenotype occurs in psoriasis, which is characterized by high plasma triglycerides (TGs) with typically normal or even low LDL-C. The extent to which cholesterol on LDL subfractions, such as small dense LDL-C (sdLDL-C), are associated with vulnerable coronary plaque characteristics in PSO remains elusive. METHODS: A recently developed equation for estimating sdLDL-C from the standard lipid panel was utilized in a PSO cohort (n = 200) with 4-year follow-up of 75 subjects. Coronary plaque burden was assessed by quantitative coronary computed tomography angiography (CCTA). Multivariate regression analyses were used for establishing associations and prognostic value of estimated sdLDL-C. RESULTS: Estimated sdLDL-C was positively associated with non-calcified burden (NCB) and fibro-fatty burden (FFB), which remained significant after multivariate adjustment for NCB (ß = 0.37; P = 0.050) and LDL-C adjustment for FFB (ß = 0.29; P < 0.0001). Of note, total LDL-C calculated by the Friedewald equation was not able to capture these associations in the study cohort. Moreover, in the regression modelling estimated sdLDL-C was significantly predicting necrotic burden progression over 4 years follow-up (P = 0.015), whereas LDL-C did not. Finally, small LDL particles (S-LDLP) and small HDL particles (S-HDLP), along with large and medium TG-rich lipoproteins (TRLPs) had the most significant positive correlation with estimated sdLDL-C. CONCLUSIONS: Estimated sdLDL-C has a stronger association than LDL-C with high-risk features of coronary atherosclerotic plaques in psoriasis patients. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov . Unique identifiers: NCT01778569.
Assuntos
Placa Aterosclerótica , Psoríase , Humanos , Placa Aterosclerótica/diagnóstico por imagem , LDL-Colesterol , Fatores de Risco , Colesterol , Psoríase/complicaçõesRESUMO
BACKGROUND: A major issue with the current management of psoriasis is our inability to predict treatment response. OBJECTIVE: Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis. METHODS: We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples. RESULTS: We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10-4) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders. CONCLUSIONS: Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.
Assuntos
Citocinas/biossíntese , Psoríase/tratamento farmacológico , Pele/imunologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Citocinas/genética , Humanos , Estudos Longitudinais , Psoríase/imunologia , RNA-Seq , Índice de Gravidade de Doença , TranscriptomaRESUMO
OBJECTIVES: Premature cardiovascular events in systemic lupus erythematosus (SLE) contribute to morbidity and mortality, with no effective preventive strategies described to date. Immune dysregulation and metabolic disturbances appear to play prominent roles in the induction of vascular disease in SLE. The peroxisome proliferator activated receptor-gamma agonist pioglitazone (PGZ suppresses vascular damage and immune dysregulation in murine lupus and improves endothelial dysfunction in other inflammatory diseases. We hypothesised that PGZ could improve vascular dysfunction and cardiometabolic parameters in SLE. METHODS: Eighty SLE subjects with mild to severe disease activity were randomised to a sequence of PGZ followed by placebo for 3 months, or vice versa, in a double-blind, cross-over design with a 2-month wash-out period. Primary endpoints were parameters of endothelial function and arterial inflammation, measured by multimodal assessments. Additional outcome measures of disease activity, neutrophil dysregulation, metabolic disturbances and gene expression studies were performed. RESULTS: Seventy-two subjects completed the study. PGZ was associated with a significant reduction in Cardio-Ankle Vascular Index (a measure of arterial stiffness) compared with placebo. Various metabolic parameters improved with PGZ, including insulin resistance and lipoprotein profiles. Circulating neutrophil extracellular trap levels also significantly decreased with PGZ compared with placebo. Most adverse events experienced while on PGZ were mild and resolved with reduction in PGZ dose. CONCLUSION: PGZ was well tolerated and induced significant improvement in vascular stiffness and cardiometabolic parameters in SLE. The results suggest that PGZ should be further explored as a modulator of cardiovascular disease risk in SLE. TRIAL REGISTRATION NUMBER: NCT02338999.
RESUMO
People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular disease (ASCVD). Proportions of vascular homing monocytes are enriched in PWH; however, little is known regarding monocyte-derived macrophages (MDMs) that may drive atherosclerosis in this population. We isolated PBMCs from people with and without HIV, and cultured these cells for 5 days in medium containing autologous serum to generate MDMs. Differential gene expression (DGE) analysis of MDMs from PWH identified broad alterations in innate immune signaling (IL-1ß, TLR expression, PPAR ßδ) and lipid processing (LXR/RXR, ACPP, SREBP1). Transcriptional changes aligned with the functional capabilities of these cells. Expression of activation markers and innate immune receptors (CD163, TLR4, and CD300e) was altered on MDMs from PWH, and these cells produced more TNFα, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) than did cells from people without HIV. MDMs from PWH also had greater lipid accumulation and uptake of oxidized LDL. PWH had increased serum levels of free fatty acids (FFAs) and ceramides, with enrichment of saturated FAs and a reduction in polyunsaturated FAs. Levels of lipid classes and species that are associated with CVD correlated with unique DGE signatures and altered metabolic pathway activation in MDMs from PWH. Here, we show that MDMs from PWH display a pro-atherogenic phenotype; they readily form foam cells, have altered transcriptional profiles, and produce mediators that likely contribute to accelerated ASCVD.
Assuntos
Aterosclerose/etiologia , Infecções por HIV/virologia , HIV/imunologia , Lipídeos/sangue , Macrófagos/patologia , Modelos Cardiovasculares , Monócitos/virologia , Aterosclerose/patologia , Estudos de Casos e Controles , HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/virologia , Monócitos/metabolismo , TranscriptomaRESUMO
Neutrophil dysregulation is implicated in the pathogenesis of systemic lupus erythematosus (SLE). SLE is characterized by elevated levels of a pathogenic neutrophil subset known as low-density granulocytes (LDGs). The origin and phenotypic, functional, and pathogenic heterogeneity of LDGs remain to be systematically determined. Transcriptomics and epigenetic assessment of lupus LDGs, autologous normal-density neutrophils, and healthy control neutrophils was performed by bulk and single-cell RNA sequencing and assay for transposase-accessible chromatin sequencing. Functional readouts were compared among neutrophil subsets. SLE LDGs display significant transcriptional and epigenetic heterogeneity and comprise 2 subpopulations of intermediate-mature and immature neutrophils, with different degrees of chromatin accessibility and differences in transcription factor motif analysis. Differences in neutrophil extracellular trap (NET) formation, oxidized mitochondrial DNA release, chemotaxis, phagocytosis, degranulation, ability to harm the endothelium, and responses to type I interferon (IFN) stimulation are evident among LDG subsets. Compared with other immune cell subsets, LDGs display the highest expression of IFN-inducible genes. Distinct LDG subsets correlate with specific clinical features of lupus and with the presence and severity of coronary artery disease. Phenotypic, functional, and pathogenic neutrophil heterogeneity are prevalent in SLE and may promote immune dysregulation and prominent vascular damage characteristic of this disease.
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Lúpus Eritematoso Sistêmico/genética , Neutrófilos/metabolismo , Adulto , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Epigênese Genética , Armadilhas Extracelulares/metabolismo , Feminino , Granulócitos/metabolismo , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA , TranscriptomaRESUMO
PURPOSE OF REVIEW: In this review, we focus on the clinical and epidemiological studies pertaining to systemic and vascular inflammation by positron emission tomography (PET) in patients with chronic inflammatory conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), human immunodeficiency virus (HIV), and psoriasis to highlight the importance of chronic systemic inflammation on vascular inflammation by PET in these disease states. RECENT FINDINGS: Recent clinical and translation advancements have demonstrated the durable relationship between chronic systemic inflammation and cardiovascular disease (CVD). In chronic inflammatory states, this relationship is robustly evident in the form of increased vascular inflammation, yet traditional risk estimates often underestimate the subclinical cardiovascular risk conferred by chronic inflammation. PET has emerged as a novel, non-invasive imaging modality capable of both quantifying the degree of systemic and vascular inflammation and detecting residual inflammation prior to cardiovascular events. We begin by demonstrating the role of inflammation in the pathogenesis of atherosclerosis, discussing how PET has been utilized to measure systemic and vascular inflammation and their effect on subclinical atherosclerosis, and finally reviewing recent applications of PET in constructing improved risk stratification for patients at high risk for stroke and CVD.
Assuntos
Artrite Reumatoide , Aterosclerose , Lúpus Eritematoso Sistêmico , Artrite Reumatoide/complicações , Aterosclerose/etiologia , Humanos , Inflamação/complicações , Inflamação/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Fatores de RiscoRESUMO
AIMS: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy. METHODS AND RESULTS: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14-25%, P < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001). CONCLUSION: The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1ß blockade with canakinumab.
Assuntos
Aterosclerose , Neutrófilos , Anticorpos Monoclonais , Aterosclerose/tratamento farmacológico , Humanos , Linfócitos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Both monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) play important roles in lipid metabolism, and diets enriched with either of these two fatty acids are associated with decreased cardiovascular risk. Conventional soybean oil (CSO), a common food ingredient, predominantly contains linoleic acid (LA; C18:2), a n-6 PUFA. Recently, a modified soybean oil (MSO) enriched in oleic acid (C18:1), a n-9 MUFA, has been developed, because of its improved chemical stability to oxidation. However, the effect of the different dietary soybean oils on cardiovascular disease remains unknown. To test whether diets rich in CSO versus MSO would attenuate atherosclerosis development, LDL receptor knock-out (LDLR-KO) mice were fed a Western diet enriched in saturated fatty acids (control), or a Western diet supplemented with 5% (w/w) LA-rich CSO or high-oleic MSO for 12 weeks. Both soybean oils contained a similar amount of linolenic acid (C18:3 n-3). The CSO diet decreased plasma lipid levels and the cholesterol content of VLDL and LDL by approximately 18% (p < 0.05), likely from increased hepatic levels of PUFA, which favorably regulated genes involved in cholesterol metabolism. The MSO diet, but not the CSO diet, suppressed atherosclerotic plaque size compared to the Western control diet (Control Western diet: 6.5 ± 0.9%; CSO diet: 6.4 ± 0.7%; MSO diet: 4.0 ± 0.5%) (p < 0.05), independent of plasma lipid level changes. The MSO diet also decreased the ratio of n-6/n-3 PUFA in the liver (Control Western diet: 4.5 ± 0.2; CSO diet: 6.1 ± 0.2; MSO diet: 2.9 ± 0.2) (p < 0.05), which correlated with favorable hepatic gene expression changes in lipid metabolism and markers of systemic inflammation. In conclusion, supplementation of the Western diet with MSO, but not CSO, reduced atherosclerosis development in LDLR-KO mice independent of changes in plasma lipids.
Assuntos
Aterosclerose , Ácidos Graxos Ômega-3 , Animais , Colesterol/metabolismo , Suplementos Nutricionais , Ácidos Graxos/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Ácidos Graxos Insaturados/metabolismo , Ácido Linoleico , Camundongos , Camundongos Knockout , Ácido Oleico , Receptores de LDL/genética , Óleo de SojaRESUMO
OBJECTIVES: Low-density granulocytes (LDGs) are a distinct subset of proinflammatory and vasculopathic neutrophils expanded in systemic lupus erythematosus (SLE). Neutrophil trafficking and immune function are intimately linked to cellular biophysical properties. This study used proteomic, biomechanical and functional analyses to further define neutrophil heterogeneity in the context of SLE. METHODS: Proteomic/phosphoproteomic analyses were performed in healthy control (HC) normal density neutrophils (NDNs), SLE NDNs and autologous SLE LDGs. The biophysical properties of these neutrophil subsets were analysed by real-time deformability cytometry and lattice light-sheet microscopy. A two-dimensional endothelial flow system and a three-dimensional microfluidic microvasculature mimetic (MMM) were used to decouple the contributions of cell surface mediators and biophysical properties to neutrophil trafficking, respectively. RESULTS: Proteomic and phosphoproteomic differences were detected between HC and SLE neutrophils and between SLE NDNs and LDGs. Increased abundance of type 1 interferon-regulated proteins and differential phosphorylation of proteins associated with cytoskeletal organisation were identified in SLE LDGs relative to SLE NDNs. The cell surface of SLE LDGs was rougher than in SLE and HC NDNs, suggesting membrane perturbances. While SLE LDGs did not display increased binding to endothelial cells in the two-dimensional assay, they were increasingly retained/trapped in the narrow channels of the lung MMM. CONCLUSIONS: Modulation of the neutrophil proteome and distinct changes in biophysical properties are observed alongside differences in neutrophil trafficking. SLE LDGs may be increasingly retained in microvasculature networks, which has important pathogenic implications in the context of lupus organ damage and small vessel vasculopathy.
Assuntos
Granulócitos/patologia , Lúpus Eritematoso Sistêmico/imunologia , Proteínas de Membrana/análise , Neutrófilos/patologia , Proteoma/análise , Estudos de Casos e Controles , Heterogeneidade Genética , Granulócitos/fisiologia , Humanos , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Microvasos/metabolismo , Neutrófilos/fisiologia , Fosforilação , ProteômicaRESUMO
OBJECTIVE: Patients with psoriasis have impaired vascular health and increased cardiovascular disease (CVD). Platelets are key players in the pathogenesis of vascular dysfunction in cardiovascular disease and represent therapeutic targets in cardiovascular prevention. The object of this study was to define the platelet phenotype and effector cell properties on vascular health in psoriasis and evaluate whether aspirin modulates the platelet-induced phenotype. Approach and Results: Platelets from psoriasis patients (n=45) exhibited increased platelet activation (relative to age- and gender-matched controls, n=18), which correlated with psoriasis skin severity. Isolated platelets from psoriasis patients demonstrated a 2- to 3-fold (P<0.01) increased adhesion to human aortic endothelial cells and induced proinflammatory transcriptional changes, including upregulation of IL 8 (interleukin 8), IL1ß, and Cox (cyclooxygenase)-2 Platelet RNA sequencing revealed an interferon signature and elevated expression of COX-1, which correlated with psoriasis disease severity (r=0.83, P=0.01). In a randomized trial of patients with psoriasis, 2 weeks of 81 mg low-dose aspirin, a COX-1 inhibitor, reduced serum thromboxane (Tx) B2 and reduced brachial vein endothelial proinflammatory transcript expression >70% compared with the no-treatment group (P<0.01). Improvement in brachial vein endothelial cell inflammation significantly correlated with change in serum TxB2 (r=0.48, P=0.02). CONCLUSIONS: In patients with psoriasis, platelets are activated and induce endothelial cell inflammation. Low-dose aspirin improved endothelial cell health in psoriasis via platelet COX-1 inhibition. These data demonstrate a previously unappreciated role of platelets in psoriasis and endothelial cell inflammation and suggests that aspirin may be effective in improving vascular health in patients with psoriasis. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03228017.
Assuntos
Plaquetas/enzimologia , Ciclo-Oxigenase 1/sangue , Células Endoteliais/enzimologia , Ativação Plaquetária , Psoríase/sangue , Adulto , Aspirina/administração & dosagem , Plaquetas/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 1/genética , Inibidores de Ciclo-Oxigenase/administração & dosagem , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adesividade Plaquetária , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Psoríase/enzimologia , Índice de Gravidade de Doença , Transdução de Sinais , Tromboxano B2/sangue , Resultado do TratamentoRESUMO
Over the past several decades, molecular imaging techniques to assess cellular processes in vivo have been integral in advancing our understanding of disease pathogenesis. 18F-fluorodeoxyglucose (18-FDG) positron emission tomography (PET) imaging in particular has shaped the field of atherosclerosis research by highlighting the importance of underlying inflammatory processes that are responsible for driving disease progression. The ability to assess physiology using molecular imaging, combining it with anatomic delineation using cardiac coronary angiography (CCTA) and magnetic resonance imaging (MRI) and lab-based techniques, provides a powerful combination to advance both research and ultimately clinical care. In this review, we demonstrate how molecular imaging studies, specifically using 18-FDG PET, have revealed that early vascular disease is a systemic process with multiple, concurrent biological mechanisms using inflammatory diseases as a basis to understand early atherosclerotic mechanisms in humans.
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Inflamação/diagnóstico , Imagem Molecular/métodos , Pesquisa Translacional Biomédica/instrumentação , Fluordesoxiglucose F18/administração & dosagem , Fluordesoxiglucose F18/uso terapêutico , Humanos , Inflamação/fisiopatologia , Imagem Molecular/tendências , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/uso terapêutico , Estresse Psicológico/complicações , Estresse Psicológico/diagnóstico por imagem , Pesquisa Translacional Biomédica/métodos , Pesquisa Translacional Biomédica/tendênciasRESUMO
BACKGROUND: Data for the effect of metabolic syndrome (MetS) on the efficacy and safety of biologic agents for psoriasis treatment are limited. OBJECTIVE: To evaluate long-term tildrakizumab efficacy, drug survival, and safety in patients with psoriasis by baseline MetS status. METHODS: Post hoc analyses of up to 3 years of efficacy data and 5 years of safety data from the phase 3, double-blind, randomized controlled reSURFACE 1 and 2 trial (NCT01722331 and NCT01729754) base and extension studies were conducted for patients receiving continuous tildrakizumab 100 or 200 mg. RESULTS: Of 338 (n = 124/214 in reSURFACE 1/2) and 307 (n = 147/160 in reSURFACE 1/2) patients continuously receiving tildrakizumab 100 and 200 mg, respectively, throughout the studies, 26/44 (21%/21%) and 34/30 (23%/19%) met MetS criteria. Proportions of patients who achieved a 75% improvement in the Psoriasis Area and Severity Index (PASI) in reSURFACE 1/2 were generally comparable among those with versus without MetS at week 52 (tildrakizumab 100 mg, 85%/86% vs 86%/94%; tildrakizumab 200 mg, 76%/87% vs 76%/87%) and through week 148. Results were similar for responders with 90% and 100% improvement in the PASI. Tildrakizumab's safety profile did not vary by MetS status. LIMITATIONS: Small sample size and post hoc analysis limit interpretation. CONCLUSION: Long-term tildrakizumab efficacy and safety were comparable between patients with and without MetS.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Síndrome Metabólica/metabolismo , Psoríase/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Comorbidade , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/epidemiologia , Psoríase/metabolismo , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
Psoriasis is a chronic, inflammatory, multisystem disease that affects up to 3.2% of the United States population. This guideline addresses important clinical questions that arise in psoriasis management and care and provides recommendations based on the available evidence. The treatment of psoriasis with topical agents and with alternative medicine will be reviewed, emphasizing treatment recommendations and the role of dermatologists in monitoring and educating patients regarding benefits as well as risks that may be associated. This guideline will also address the severity assessment methods of psoriasis in adults.
Assuntos
Terapias Complementares/métodos , Fármacos Dermatológicos/administração & dosagem , Dermatologia/métodos , Psoríase/terapia , Academias e Institutos/normas , Administração Cutânea , Terapia Combinada/métodos , Terapia Combinada/normas , Terapias Complementares/normas , Dermatologia/normas , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/normas , Fundações/normas , Humanos , Educação de Pacientes como Assunto/normas , Psoríase/diagnóstico , Índice de Gravidade de Doença , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Psoriasis is associated with a heightened risk of cardiovascular disease and higher prevalence of metabolic syndrome. OBJECTIVE: Investigate the effect of metabolic syndrome and its factors on early coronary artery disease assessed as noncalcified coronary burden by coronary computed tomography angiography in psoriasis. METHODS: This cross-sectional study consisted of 260 participants with psoriasis and coronary computed tomography angiography characterization. Metabolic syndrome was defined according to the harmonized International Diabetes Federation criteria. RESULTS: Of the 260 participants, 80 had metabolic syndrome (31%). The metabolic syndrome group had a higher burden of cardiometabolic disease, systemic inflammation, noncalcified coronary burden, and high-risk coronary plaque. After adjusting for Framingham risk score, lipid-lowering therapy, and biologic use, metabolic syndrome (ß = .31; P < .001) and its individual factors of waist circumference (ß = .33; P < .001), triglyceride levels (ß = .17; P = .005), blood pressure (ß = .18; P = .005), and fasting glucose (ß = .17; P = .009) were significantly associated with noncalcified coronary burden. After adjusting for all other metabolic syndrome factors, blood pressure and waist circumference remained significantly associated with noncalcified coronary burden. LIMITATIONS: Observational nature with limited ability to control for confounders. CONCLUSIONS: In psoriasis, individuals with metabolic syndrome had more cardiovascular disease risk factors, systemic inflammation, and noncalcified coronary burden. Efforts to increase metabolic syndrome awareness in psoriasis should be undertaken to reduce the heightened cardiovascular disease risk.
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Doença da Artéria Coronariana/epidemiologia , Síndrome Metabólica/epidemiologia , Psoríase/complicações , Adulto , Pressão Sanguínea , Fatores de Risco Cardiometabólico , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Psoríase/sangue , Psoríase/metabolismo , Medição de Risco/estatística & dados numéricos , Tomografia Computadorizada por Raios X , Triglicerídeos/sangue , Circunferência da CinturaRESUMO
The effects of cell size, shape and deformability on cellular function have long been a topic of interest. Recently, mechanical phenotyping technologies capable of analysing large numbers of cells in real time have become available. This has important implications for biology and medicine, especially haemato-oncology and immunology, as immune cell mechanical phenotyping, immunologic function, and malignant cell transformation are closely linked and potentially exploitable to develop new diagnostics and therapeutics. In this review, we introduce the technologies used to analyse cellular mechanical properties and review emerging findings following the advent of high throughput deformability cytometry. We largely focus on cells from the myeloid lineage, which are derived from the bone marrow and include macrophages, granulocytes and erythrocytes. We highlight advances in mechanical phenotyping of cells in suspension that are revealing novel signatures of human blood diseases and providing new insights into pathogenesis of these diseases. The contributions of mechanical phenotyping of cells in suspension to our understanding of drug mechanisms, identification of novel therapeutics and monitoring of treatment efficacy particularly in instances of haematologic diseases are reviewed, and we suggest emerging topics of study to explore as high throughput deformability cytometers become prevalent in laboratories across the globe.
Assuntos
Células Mieloides/imunologia , Fenótipo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Fenômenos Biomecânicos , Elasticidade , Citometria de Fluxo , Glucocorticoides/farmacologia , Humanos , Microscopia de Força Atômica , Células Mieloides/efeitos dos fármacos , Neoplasias/tratamento farmacológicoRESUMO
OBJECTIVES: Little is understood about associations between neighborhood characteristics and depression, a cardiovascular disease (CVD) risk factor, in diverse populations. We examined relationships between perceived/objective neighborhood characteristics, depression, and CVD markers within the Washington, DC CV Health/Needs Assessment, an evaluation among predominantly African-American (AA) adults in resource-limited DC communities. METHOD: Factor analysis of overall neighborhood environment perception (NEP) identified three NEP sub-scores:1) violence; 2) physical/social environment; 3) social cohesion (higher score = more favorable perception). Objective neighborhood characteristics were measured by geospatially-derived scores of walkability, transportation, and crime. Depression was defined by the revised Center for Epidemiologic Studies Depression Scale (CESD-R). We used linear-regression modeling to examine neighborhood measures and CESD-R associations. To investigate a subsequent connection with CVD risk, we examined relationships between CESD-R and CVD-associated cytokines in a population subset. RESULTS: Participants (N = 99; mean age = 59.06; 99% AA) had a mean CESD-R score = 5.8(SD = 8.88). In adjusted models, CESD-R scores decreased by 0.20 units (p = 0.01) for every overall NEP unit-increase. Perceived physical/social environment (ß = -0.34, p = 0.04) and social cohesion (ß = -0.82, p = 0.01) were related to CESD-R while perceived violence was not (ß = -0.28, p = 0.1). Of objective neighborhood environment measures (i.e. walk, transit, bike, personal crime, and property crime scores), only property crime score was associated with depression (ß = 4.99, p < 0.03). In population subset (n = 42), higher CESD-R associated with higher IL-1ß (ß = 21.25, p < 0.01) and IL-18 (ß = 0.006, p = 0.01). CONCLUSION: Favorable neighborhood perceptions are related to lower depressive symptoms in a predominantly AA cohort from Washington, DC resource-limited communities. Neighborhood perceptions appear to be strongly associated with depressive symptoms compared to objective characteristics. Increasing CESD-R scores were related to higher pro-inflammatory markers. Improving neighborhood perceptions may be beneficial to psychological well-being and CV health for urban minority residents.