RESUMO
BACKGROUND AND AIMS: The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. METHODS: The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9-/- mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. RESULTS: In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9-/- mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9-/- mice, confirming target specificity. CONCLUSION: Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis.
Assuntos
Endotoxemia , Cardiopatias , Disfunção Ventricular Esquerda , Humanos , Camundongos , Animais , Endotoxemia/complicações , Endotoxemia/tratamento farmacológico , Lipopolissacarídeos , Calgranulina A/fisiologia , Calgranulina B/genética , Miocárdio , Inflamação/tratamento farmacológicoRESUMO
RATIONALE: Neutrophils likely contribute to the thrombotic complications of human atheromata. In particular, neutrophil extracellular traps (NETs) could exacerbate local inflammation and amplify and propagate arterial intimal injury and thrombosis. PAD4 (peptidyl arginine deiminase 4) participates in NET formation, but an understanding of this enzyme's role in atherothrombosis remains scant. OBJECTIVE: This study tested the hypothesis that PAD4 and NETs influence experimental atherogenesis and in processes implicated in superficial erosion, a form of plaque complication we previously associated with NETs. METHODS AND RESULTS: Bone marrow chimeric Ldlr deficient mice reconstituted with either wild-type or PAD4-deficient cells underwent studies that assessed atheroma formation or procedures designed to probe mechanisms related to superficial erosion. PAD4 deficiency neither retarded fatty streak formation nor reduced plaque size or inflammation in bone marrow chimeric mice that consumed an atherogenic diet. In contrast, either a PAD4 deficiency in bone marrow-derived cells or administration of DNaseI to disrupt NETs decreased the extent of arterial intimal injury in mice with arterial lesions tailored to recapitulate characteristics of human atheroma complicated by erosion. CONCLUSIONS: These results indicate that PAD4 from bone marrow-derived cells and NETs do not influence chronic experimental atherogenesis, but participate causally in acute thrombotic complications of intimal lesions that recapitulate features of superficial erosion.
Assuntos
Armadilhas Extracelulares/fisiologia , Hidrolases/fisiologia , Placa Aterosclerótica/etiologia , Trombose/etiologia , Animais , Transplante de Medula Óssea , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/patologia , Morte Celular , Desoxirribonuclease I/farmacologia , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Hidrolases/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologia , Osteomielite/etiologia , Placa Aterosclerótica/patologia , Proteína-Arginina Desiminase do Tipo 4 , Trombose/prevenção & controle , Túnica Íntima/lesõesRESUMO
OBJECTIVE: MR (mineralocorticoid receptor) activation is associated with cardiovascular ischemia in humans. This study explores the role of the MR in atherosclerotic mice of both sexes and identifies a sex-specific role for endothelial cell (EC)-MR in vascular inflammation. Approach and Results: In the AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9) mouse atherosclerosis model, MR inhibition attenuated vascular inflammation in males but not females. Further studies comparing male and female littermates with intact MR or EC-MR deletion revealed that although EC-MR deletion did not affect plaque size in either sex, it reduced aortic arch inflammation specifically in male mice as measured by flow cytometry. Moreover, MR-intact females had larger plaques but were protected from vascular inflammation compared with males. Intravital microscopy of the mesenteric vasculature demonstrated that EC-MR deletion attenuated TNFα (tumor necrosis factor α)-induced leukocyte slow rolling and adhesion in males, while females exhibited fewer leukocyte-endothelial interactions with no additional effect of EC-MR deletion. These effects corresponded with decreased TNFα-induced expression of the endothelial adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and E-selectin in males with EC-MR deletion compared with MR-intact males and females of both genotypes. These observations were also consistent with MR and estrogen regulation of ICAM-1 transcription and E-selectin expression in primary cultured mouse ECs and human umbilical vein ECs. CONCLUSIONS: In male mice, EC-MR deletion attenuates leukocyte-endothelial interactions, plaque inflammation, and expression of E-selectin and ICAM-1, providing a potential mechanism by which the MR promotes vascular inflammation. In females, plaque inflammation and leukocyte-endothelial interactions are decreased relative to males and EC-MR deletion is not protective.
Assuntos
Aterosclerose/complicações , Células Endoteliais/fisiologia , Receptores de Mineralocorticoides/fisiologia , Vasculite/etiologia , Animais , Células Cultivadas , Selectina E/genética , Feminino , Molécula 1 de Adesão Intercelular/genética , Leucócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Caracteres SexuaisRESUMO
Dendritic cells (DCs) have been implicated as important regulators of innate and adaptive inflammation in many diseases, including atherosclerosis. However, the molecular mechanisms by which DCs mitigate or promote inflammatory pathogenesis are only partially understood. Previous studies have shown an important anti-inflammatory role for the transcription factor Krüppel-like factor 2 (KLF2) in regulating activation of various cell types that participate in atherosclerotic lesion development, including endothelial cells, macrophages, and T cells. We used a pan-DC, CD11c-specific cre-lox gene knockout mouse model to assess the role of KLF2 in DC activation, function, and control of inflammation in the context of hypercholesterolemia and atherosclerosis. We found that KLF2 deficiency enhanced surface expression of costimulatory molecules CD40 and CD86 in DCs and promoted increased T cell proliferation and apoptosis. Transplant of bone marrow from mice with KLF2-deficient DCs into Ldlr-/- mice aggravated atherosclerosis compared with control mice, most likely due to heightened vascular inflammation evidenced by increased DC presence within lesions, enhanced T cell activation and cytokine production, and increased cell death in atherosclerotic lesions. Taken together, these data indicate that KLF2 governs the degree of DC activation and hence the intensity of proatherogenic T cell responses.
Assuntos
Aterosclerose/imunologia , Células da Medula Óssea/fisiologia , Células Dendríticas/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , Linfócitos T/imunologia , Animais , Transplante de Medula Óssea , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imunidade Celular , Fatores de Transcrição Kruppel-Like/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/genéticaRESUMO
OBJECTIVE: T cell immunoglobulin and mucin domain (Tim) proteins are expressed by numerous immune cells, recognize phosphatidylserine on apoptotic cells, and function as costimulators or coinhibitors. Tim-1 is expressed by activated T cells but is also found on dendritic cells and B cells. Tim-4, present on macrophages and dendritic cells, plays a critical role in apoptotic cell clearance, regulates the number of phosphatidylserine-expressing activated T cells, and is genetically associated with low low-density lipoprotein and triglyceride levels. Because these functions of Tim-1 and Tim-4 could affect atherosclerosis, their modulation has potential therapeutic value in cardiovascular disease. APPROACH AND RESULTS: ldlr(-/-) mice were fed a high-fat diet for 4 weeks while being treated with control (rat immunoglobulin G1) or anti-Tim-1 (3D10) or -Tim-4 (21H12) monoclonal antibodies that block phosphatidylserine recognition and phagocytosis. Both anti-Tim-1 and anti-Tim-4 treatments enhanced atherosclerosis by 45% compared with controls by impairment of efferocytosis and increasing aortic CD4(+)T cells. Consistently, anti-Tim-4-treated mice showed increased percentages of activated T cells and late apoptotic cells in the circulation. Moreover, in vitro blockade of Tim-4 inhibited efferocytosis of oxidized low-density lipoprotein-induced apoptotic macrophages. Although anti-Tim-4 treatment increased T helper cell (Th)1 and Th2 responses, anti-Tim-1 induced Th2 responses but dramatically reduced the percentage of regulatory T cells. Finally, combined blockade of Tim-1 and Tim-4 increased atherosclerotic lesion size by 59%. CONCLUSIONS: Blockade of Tim-4 aggravates atherosclerosis likely by prevention of phagocytosis of phosphatidylserine-expressing apoptotic cells and activated T cells by Tim-4-expressing cells, whereas Tim-1-associated effects on atherosclerosis are related to changes in Th1/Th2 balance and reduced circulating regulatory T cells.
Assuntos
Anticorpos Monoclonais/toxicidade , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Linfócitos T CD4-Positivos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Receptores de LDL/deficiência , Animais , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apoptose/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Receptor Celular 1 do Vírus da Hepatite A , Lipoproteínas LDL/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Placa Aterosclerótica , Receptores de LDL/genética , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologiaRESUMO
Increased glucose levels are associated with the generation of advanced glycation endproduct (AGE) modifications. Interaction between AGE-modified plaque components and immune cells is believed to have an important role in the development of vascular complications in diabetes. Methylglyoxal (MGO) is one type of reactive aldehyde that gives rise to AGE modification. The present study analyzed whether autoantibodies against MGO-modified epitopes of the low-density lipoprotein apolipoprotein B (apoB) 100 predict cardiovascular events. A library consisting of 302 peptides comprising the complete apoB100 molecule was screened to identify peptides targeted by MGO-specific autoantibodies. Peptide (p) 220 (apoB amino acids 3286-3305) was identified as a major target. Baseline IgM and IgG against MGO-peptide 220 (p220) were measured in 700 individuals from the Malmö Diet and Cancer Cohort. A total of 139 cardiovascular events were registered during the 15-y follow-up period. Controlling for major cardiovascular risk factors demonstrated that subjects in the lowest tertile of MGO-p220 IgM had an increased risk for cardiovascular events (hazard ratio [95% confidence interval]: 2.07 [1.22-3.50]; p(trend) = 0.004). Interestingly, the association between MGO-p220 IgM and cardiovascular events remained and even tended to become stronger when subjects with prevalent diabetes were excluded from the analysis (2.51 [1.37-4.61]; p(trend) = 0.002). MGO-p220 IgM was inversely associated with blood glucose, but not with oxidized low-density lipoprotein. Finally, we demonstrate that anti-MGO-p220 IgM is produced by B1 cells. These data show that subjects with low levels of IgM recognizing MGO-modified p220 in apoB have an increased risk to develop cardiovascular events and that this association is present in nondiabetic subjects.
Assuntos
Apolipoproteína B-100/imunologia , Doenças Cardiovasculares/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Aldeído Pirúvico/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos/sangue , Anticorpos/imunologia , Aterosclerose/fisiopatologia , Autoanticorpos/imunologia , Linfócitos B/imunologia , Glicemia/análise , Doenças Cardiovasculares/diagnóstico , Citocinas/sangue , Diabetes Mellitus/imunologia , Feminino , Produtos Finais de Glicação Avançada/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Lipoproteínas LDL/sangue , Masculino , Aldeído Pirúvico/farmacologia , Fatores de RiscoRESUMO
OBJECTIVE: Innate lymphoid cells (ILCs) are a newly discovered subset of immune cells that promote tissue homeostasis and protect against pathogens. ILCs produce cytokines also produced by T lymphocytes that have been shown to affect atherosclerosis, but the influence of ILCs on atherosclerosis has not been explored. APPROACH AND RESULTS: We demonstrate that CD25(+) ILCs that produce type 2 cytokines (ILC2s) are present in the aorta of atherosclerotic immunodeficient ldlr(-/-)rag1(-/-) mice. To investigate the role of ILCs in atherosclerosis, ldlr(-/-)rag1(-/-) mice were concurrently fed an atherogenic diet and treated with either ILC-depleting anti-CD90.2 antibodies or IL-2/anti-IL-2 complexes that expand CD25(+) ILCs. Lesion development was not affected by anti-CD90.2 treatment, but was reduced in IL-2/anti-IL-2-treated mice. These IL-2-treated mice had reduced very low-density lipoprotein cholesterol and increased triglycerides compared with controls and reduced apolipoprotein B100 gene expression in the liver. IL-2/anti-IL-2 treatment caused expansion of ILC2s in aorta and other tissues, elevated levels of IL-5, systemic eosinophila, and hepatic eosinophilic inflammation. Blockade of IL-5 reversed the IL-2 complex-induced eosinophilia but did not change lesion size. CONCLUSIONS: This study demonstrates that expansion of CD25-expressing ILCs by IL-2/anti-IL-2 complexes leads to a reduction in very low-density lipoprotein cholesterol and atherosclerosis. Global depletion of ILCs by anti-CD90.2 did not significantly affect lesion size indicating that different ILC subsets may have divergent effects on atherosclerosis.
Assuntos
Anticorpos/farmacologia , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-2/farmacologia , Linfócitos/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteína B-100 , Apolipoproteínas B/sangue , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/sangue , VLDL-Colesterol/sangue , Modelos Animais de Doenças , Eosinofilia/imunologia , Eosinofilia/metabolismo , Eosinofilia/prevenção & controle , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-5/antagonistas & inibidores , Interleucina-5/sangue , Interleucina-5/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/deficiência , Receptores de LDL/genética , Triglicerídeos/sangueRESUMO
Increased production of autoantibodies is a characteristic feature of systemic lupus erythematosus (SLE) and there is evidence that several of these autoantibodies may contribute to increased cardiovascular disease (CVD) in SLE. Autoantibodies against the apolipoprotein (apo) B-100 peptides p45 and p210 have been associated with a lower CVD risk in non-SLE cohorts. The aim of the present study was to investigate how SLE affects the occurrence of these potentially protective autoantibodies. The study cohort consisted of 434 SLE patients and 322 age- and sex-matched population controls. Antibodies against native and malondialdehyde (MDA)-modified p45 and p210 were measured by enzyme-linked immunosorbent assay (ELISA). SLE patients had significantly lower levels of p210 immunoglobulin (Ig)G and p45 IgM (both the native and malondialdehyde (MDA)-modified forms). SLE patients with manifest CVD (myocardial infarction, ischaemic cerebrovascular disease or peripheral vascular disease) had lower levels p210 IgG and p45 IgM than SLE patients without CVD. Decreased levels of these autoantibodies were also observed in SLE patients with permanent organ damage, as assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (SDI). The present findings show that patients with SLE, a condition generally characterized by abundance of autoantibodies of multiple specificities, have reduced levels of antibodies against the apo B-100 antigens p45 and p210 and that the levels of these antibodies are reduced further in SLE patients with CVD. These observations suggest the possibility that an impaired antibody-mediated removal of damaged LDL particles may contribute to the development of vascular complications and organ damage in SLE.
Assuntos
Apolipoproteína B-100/imunologia , Autoanticorpos/imunologia , Doenças Cardiovasculares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Doenças Cardiovasculares/sangue , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Modelos Logísticos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Malondialdeído/imunologia , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVE: Experimental studies in mice have attributed T-helper (Th) 1 and Th2 cells important roles in atherosclerosis, but the clinical importance of these cells in cardiovascular disease (CVD) remains to be clarified. Here, we investigated associations between Th1 and Th2 cells, carotid intima-media thickness, and cardiovascular risk. METHODS AND RESULTS: Blood drawn at baseline and incident cardiovascular events during 15-year follow-up were assessed in 700 participants. Baseline Th1 (CD3(+)CD4(+)interferon-γ(+)) and Th2 (CD3(+)CD4(+)interleukin-4(+)) cells were analyzed by flow cytometry, and cytokine-release from activated mononuclear leukocytes was measured by multiplex technology. High numbers of Th2 cells were independently associated with decreased mean common carotid intima-media thickness. High numbers of Th2 cells were also independently associated with a reduced risk of acute myocardial infarction in women (hazard ratio, 0.19; 95% confidence interval, 0.06-0.56; P=0.002 for the highest versus the lowest tertile of Th2 cells). Moreover, release of the Th2 cytokine interleukin-4 from activated mononuclear leukocytes was independently associated with a reduced risk of CVD. No independent associations between Th1 cells and carotid intima-media thickness or CVD risk were found. CONCLUSIONS: Our observations provide the first clinical evidence for a protective role of Th2 immunity in CVD. They also suggest this protection is more prominent in women than in men. In spite of convincing evidence from experimental studies, we found no support for a role of Th1 immunity in CVD.
Assuntos
Infarto do Miocárdio/imunologia , Acidente Vascular Cerebral/imunologia , Células Th2/imunologia , Idoso , Biomarcadores/sangue , Espessura Intima-Media Carotídea , Células Cultivadas , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Humanos , Imunoensaio , Incidência , Interferon gama/sangue , Interleucina-4/sangue , Estimativa de Kaplan-Meier , Modelos Lineares , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Suécia/epidemiologia , Células Th1/imunologia , Fatores de TempoRESUMO
AIMS: The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis. METHODS AND RESULTS: Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E-deficient (Apoe-/-) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade. CONCLUSION: Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.
Assuntos
Aterosclerose , Inflamação , Proteína Acessória do Receptor de Interleucina-1 , Placa Aterosclerótica , Animais , Feminino , Humanos , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Inflamação/genética , Inflamação/patologia , Proteína Acessória do Receptor de Interleucina-1/antagonistas & inibidores , Proteína Acessória do Receptor de Interleucina-1/genética , Proteína Acessória do Receptor de Interleucina-1/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Transdução de SinaisRESUMO
BACKGROUND AND AIMS: The homeostatic chemokines CCL21 and CCL19 have been explored as biomarkers in cardiovascular disease prediction in patients with established cardiovascular disease, but associations between these chemokines and first-time coronary event incidence have not been investigated before. Here, we explored associations between CCL21 or CCL19 and first-time incident coronary events in the general population-based Malmö Diet and Cancer cohort with two decades of follow-up. METHODS: CCL21 and CCL19 levels in plasma were analysed with ELISA and proximity extension assay and associations with disease incidence were explored with conditional logistic regression in a nested case-control cohort (CCL21; n = 676) and with Cox regression in a population-based cohort (CCL19; n = 4636). RESULTS: High CCL21 levels in plasma were associated with incident first-time coronary events independently of traditional risk factors (odds ratio of 2.64 with 95% confidence interval 1.62-4.31, p < 0.001, comparing the highest versus the lowest tertile of CCL21), whereas CCL19 was not. CCL19 was, however, associated with incident heart failure, as well as increased all-cause, cardiovascular and cancer mortality independently of age and sex. CONCLUSIONS: Even though CCL21 and CCL19 both signal through CCR7, these chemokines may not be interchangeable as disease predictors and CCL21 could be used for prediction of future coronary events in individuals without any previous coronary heart disease history.
Assuntos
Doenças Cardiovasculares , Doença das Coronárias , Humanos , Quimiocina CCL21 , Quimiocinas , Estudos Prospectivos , Receptores CCR7RESUMO
Aims: Invariant natural killer T (iNKT) cells, a T cell subset that is CD1d-restricted and expresses a semi-invariant T cell receptor, have been proposed to contribute to dyslipidaemia-driven cardiovascular disease due to their ability to specifically recognize lipid antigens. Studies in mice have attributed pro-atherogenic properties to iNKT cells, but studies in humans investigating associations of iNKT cells with incident coronary events (CE) are lacking. Methods and results: Here, we used flow cytometry to enumerate circulating iNKT cells (CD3+ CD1d-PBS57-Tetramer+) in a case-control cohort nested within the prospective population-based Malmö Diet and Cancer Study (n = 416) to explore associations with incident first-time CE during a median follow-up of 14 years. We found a significant inverse association between CD4- and CD8- double negative (DN) iNKT cells and incident CE, with an odds ratio of 0.62 [95% confidence interval (CI) 0.38-0.99; P = 0.046] comparing the highest vs. the lowest tertile of DN iNKT cells. The association remained significant after adjustment for cardiovascular risk factors with an odds ratio of 0.57 (95% CI 0.33-0.99; P = 0.046). In contrast, total iNKT cells were not significantly associated with incident CE after adjustment, with an odds ratio of 0.74 (95% CI 0.43-1.27; P = 0.276). Conclusion: Our findings indicate that animal studies suggesting an atherosclerosis-promoting role for iNKT cells may not translate to human cardiovascular disease as our data show an association between high circulating numbers of DN iNKT cells and decreased risk of incident CE.
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Despite improvements in cancer survival, cancer therapy-related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors.
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Background: The immune checkpoint receptor lymphocyte-activation gene 3 (LAG3) is a new target for immune checkpoint blockade (ICB), but the effects of LAG3 on atherosclerosis are not known. Objectives: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis. Methods: To study the role of LAG3 in atherosclerosis, we investigated both bone marrow chimeras lacking LAG3 in hematopoietic cells as well as global Lag3 -/- knockout mice. Effects of anti-LAG3 monoclonal antibody monotherapy and combination therapy with anti-programmed cell death protein 1 (PD-1) were tested in hypercholesterolemic low-density lipoprotein receptor knockout (Ldlr -/- ) mice and evaluated by histology and flow cytometry. Results: LAG3-deficiency or treatment with blocking anti-LAG3 monoclonal antibodies led to increased levels of both interferon gamma-producing T helper 1 cells and effector/memory T cells, balanced by increased levels of regulatory T cells. Plaque size was affected by neither LAG3 deficiency nor LAG3 blockade, although density of T cells in plaques was 2-fold increased by loss of LAG3. Combination therapy of anti-PD-1 and anti-LAG3 had an additive effect on T cell activation and cytokine production and promoted plaque infiltration of T cells. Conclusions: Loss of LAG3 function promoted T cell activation and accumulation in plaques while not affecting plaque burden. Our report supports further clinical studies investigating cardiovascular risk in patients treated with anti-LAG3 ICB.
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The SIRPα-CD47 axis plays an important role in T cell recruitment to sites of immune reaction and inflammation but its role in T cell antigen priming is incompletely understood. Employing OTII TCR transgenic mice bred to Cd47-/- (Cd47KO) or SKI mice, a knock-in transgenic animal expressing non-signaling cytoplasmic-truncated SIRPα, we investigated how the SIRPα-CD47 axis contributes to antigen priming. Here we show that adoptive transfer of Cd47KO or SKI Ova-specific CD4+ T cells (OTII) into Cd47KO and SKI recipients, followed by Ova immunization, elicited reduced T cell division and proliferation indices, increased apoptosis, and reduced expansion compared to transfer into WT mice. We confirmed prior reports that splenic T cell zone, CD4+ conventional dendritic cells (cDCs) and CD4+ T cell numbers were reduced in Cd47KO and SKI mice. We report that in vitro derived DCs from Cd47KO and SKI mice exhibited impaired migration in vivo and exhibited reduced CD11c+ DC proximity to OTII T cells in T cell zones after Ag immunization, which correlates with reduced TCR activation in transferred OTII T cells. These findings suggest that reduced numbers of CD4+ cDCs and their impaired migration contributes to reduced T cell-DC proximity in splenic T cell zone and reduced T cell TCR activation, cell division and proliferation, and indirectly increased T cell apoptosis.
Assuntos
Antígeno CD47 , Receptores Imunológicos , Baço , Animais , Antígenos , Antígeno CD47/genética , Antígeno CD47/metabolismo , Comunicação Celular , Células Dendríticas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Baço/imunologia , Baço/metabolismo , Linfócitos T/metabolismoRESUMO
BACKGROUND AND AIMS: The relationship between inflammation and lipid metabolism is complex and bidirectional. Lymphocyte-driven inflammation has been shown to modulate both atherosclerotic plaque development and cholesterol levels, but the mechanisms are incompletely understood. METHODS: The cardiometabolic effects of IL-2Rßγ signalling in atherosclerotic Apoe-/- mice were investigated by treatment with an agonistic IL-2Rßγ-targeting IL-2/anti-IL-2 complex or a monoclonal anti-CD122 (IL-2Rß) blocking antibody. RESULTS: Administration of IL-2Rßγ agonistic IL-2/anti-IL-2 complexes to Apoe-/- mice augmented opposing arms of the adaptive immune system. Expansion of effector/memory T cells and increased levels of circulating pro-inflammatory cytokines were observed along with elevated levels of regulatory T cells and IL-10. Notably, IL-2/anti-IL-2 treatment did not affect plaque size but decreased levels of plasma cholesterol. The cholesterol lowering effect of IL-2Rßγ agonism was not affected by anti-CD8 or anti-NK1.1 depleting antibody treatment but was contingent on the presence of adaptive immunity. Expression of multiple liver X receptor (LXR)-related genes, including Pltp and Srebp1c in the liver, was decreased by IL-2/anti-IL-2 treatment. Although IL-2Rßγ agonism lowered cholesterol levels, blocking IL-2Rßγ signalling using an anti-CD122 monoclonal antibody did not impact cholesterol levels or plaque burden in Apoe-/- mice. CONCLUSIONS: Elevated IL-2Rßγ signalling results in activation of both inflammatory and regulatory lymphocytes with a net zero effect on atherosclerosis and decreased plasma cholesterol levels. Changes in cholesterol levels were associated with reductions in hepatic LXR-related gene expression. Further studies are needed to investigate the clinical significance of IL-2 mediated modulation of hepatic LXR signalling in inflammatory disorders.
Assuntos
Aterosclerose , Subunidade beta de Receptor de Interleucina-2 , Placa Aterosclerótica , Animais , Colesterol , Inflamação , Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoERESUMO
Type 2 diabetes mellitus is associated with an elevated risk of cardiovascular disease, but the mechanism through which diabetes contributes to cardiovascular disease development remains incompletely understood. In this study, we compared the association of circulating regulatory T cells, naïve T cells, effector memory T cells or central memory T cells with cardiovascular disease in patients with and without type 2 diabetes mellitus. Percentage of circulating T cell subsets was analysed by flow cytometry in type 2 diabetes mellitus subjects with and without prevalent cardiovascular disease as well as in non-diabetic subjects with and without prevalent cardiovascular disease from the Malmö SUMMIT cohort. Subjects with type 2 diabetes mellitus had elevated percentages of effector memory T cells (CD4+CD45RO+CD62L-; 21.8% ± 11.2% vs 17.0% ± 9.2% in non-type 2 diabetes mellitus, p < 0.01) and central memory T cells (CD4+CD45RO+CD62L+; 38.0% ± 10.7% vs 36.0% ± 9.5% in non-type 2 diabetes mellitus, p < 0.01). In contrast, the frequency of naïve T cells was reduced (CD4+CD45RO-CD62L+, 35.0% ± 16.5% vs 42.9% ± 14.4% in non-type 2 diabetes mellitus, p < 0.001). The proportion of effector memory T cells was increased in type 2 diabetes mellitus subjects with cardiovascular disease as compared to those without (26.4% ± 11.5% vs 18.4% ± 10.2%, p < 0.05), while no difference in regulatory T cells was observed between these two patient groups. This study identifies effector memory T cells as a potential cellular biomarker for cardiovascular disease among subjects with type 2 diabetes mellitus, suggesting a state of exacerbated immune activation in type 2 diabetes mellitus patients with cardiovascular disease.
Assuntos
Doenças Cardiovasculares/imunologia , Diabetes Mellitus Tipo 2/imunologia , Memória Imunológica , Linfócitos T Reguladores/imunologia , Idoso , Contagem de Linfócito CD4 , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Fenótipo , Prevalência , Suécia/epidemiologiaRESUMO
CD47, also known as integrin-associated protein (IAP), is a transmembrane protein with multiple biological functions including regulation of efferocytosis and leukocyte trafficking. In this study we investigated the effect of CD47-deficiency on atherosclerosis using a model of adeno-associated virus (AAV)-induced hypercholesterolemia. We observed increased plaque formation in CD47 null mice compared to wild-type controls. Loss of CD47 caused activation of dendritic cells, T cells and natural killer (NK) cells, indicating an important role for CD47 in regulating immunity. In particular, Cd47 deficiency increased the proportion of IFN-γ producing CD90+ NK cells. Treatment with depleting anti-NK1.1 monoclonal antibody (mAb), but not depleting anti-CD4/CD8 mAbs, equalized atherosclerotic burden, suggesting NK cells were involved in the enhanced disease in Cd47 deficient mice. Additional studies revealed that levels of CD90+ and IFN-γ+ NK cells were expanded in atherosclerotic aorta and that CD90+ NK cells produce more IFN-γ than CD90- NK cells. Finally, we demonstrate that anti-CD47 (MIAP410) causes splenomegaly and activation of DCs and T cells, without affecting NK cell activation. In summary, we demonstrate that loss of CD47 causes increased lymphocyte activation that results in increased atherosclerosis.
Assuntos
Aterosclerose/etiologia , Antígeno CD47/deficiência , Ativação Linfocitária , Animais , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/metabolismoRESUMO
Aims: The role of CD4+ T cells in atherosclerosis has been shown to be dependent on cytokine cues that regulate lineage commitment into mature T helper sub-sets. In this study, we tested the roles of IL-1R1 and MyD88 signalling in CD4+ T cells in atherosclerosis. Methods and results: We transferred apoe-/-myd88+/+ or apoe-/-myd88-/- CD4+ T cells to T- and B-cell-deficient rag1-/-apoe-/- mice fed high fat diet. Mice given apoe-/-myd88-/- CD4+ T cells exhibited reduced atherosclerosis compared with mice given apoe-/-myd88+/+ CD4+ T cells. CD4+ T cells from apoe-/-myd88-/- produced less IL-17 but similar levels of IFN-γ. Treatment of human CD4+ T cells with a MyD88 inhibitor inhibited IL-17 secretion in vitro. Transfer of il1r1-/- CD4+ T cells recapitulated the phenotype seen by transfer of myd88-/- CD4+ T cells with reduced lesion development and a reduction in Th17 and IL-17 production compared with wild type CD4+ T cell recipients. Relative collagen content of lesions was reduced in mice receiving il1r1-/- CD4+ T cells. Conclusion: We demonstrate that both IL1R and MyD88 signalling in CD4+ T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels.