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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.
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Aterosclerosis , Inflamación , Proteína Accesoria del Receptor de Interleucina-1 , Placa Aterosclerótica , Animales , Femenino , Humanos , Masculino , Ratones , Antiinflamatorios/farmacología , Aterosclerosis/genética , Aterosclerosis/patología , Modelos Animales de Enfermedad , Inflamación/genética , Inflamación/patología , Proteína Accesoria del Receptor de Interleucina-1/antagonistas & inhibidores , Proteína Accesoria del Receptor de Interleucina-1/genética , Proteína Accesoria del Receptor de Interleucina-1/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/patología , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Transducción de SeñalRESUMEN
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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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.
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Endotoxemia , Cardiopatías , Disfunción Ventricular Izquierda , Humanos , Ratones , Animales , Endotoxemia/complicaciones , Endotoxemia/tratamiento farmacológico , Lipopolisacáridos , Calgranulina A/fisiología , Calgranulina B/genética , Miocardio , Inflamación/tratamiento farmacológicoRESUMEN
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.
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Enfermedades Cardiovasculares , Enfermedad Coronaria , Humanos , Quimiocina CCL21 , Quimiocinas , Estudios Prospectivos , Receptores CCR7RESUMEN
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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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.
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Antígeno CD47 , Receptores Inmunológicos , Bazo , Animales , Antígenos , Antígeno CD47/genética , Antígeno CD47/metabolismo , Comunicación Celular , Células Dendríticas , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Bazo/inmunología , Bazo/metabolismo , Linfocitos T/metabolismoRESUMEN
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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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.
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Aterosclerosis , Subunidad beta del Receptor de Interleucina-2 , Placa Aterosclerótica , Animales , Colesterol , Inflamación , Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoERESUMEN
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.
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Aterosclerosis/etiología , Antígeno CD47/deficiencia , Activación de Linfocitos , Animales , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Células Asesinas Naturales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T/metabolismoRESUMEN
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.
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Aterosclerosis/complicaciones , Células Endoteliales/fisiología , Receptores de Mineralocorticoides/fisiología , Vasculitis/etiología , Animales , Células Cultivadas , Selectina E/genética , Femenino , Molécula 1 de Adhesión Intercelular/genética , Leucocitos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Caracteres SexualesRESUMEN
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.
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Enfermedades Cardiovasculares/inmunología , Diabetes Mellitus Tipo 2/inmunología , Memoria Inmunológica , Linfocitos T Reguladores/inmunología , Anciano , Recuento de Linfocito CD4 , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Citometría de Flujo , Humanos , Masculino , Fenotipo , Prevalencia , Suecia/epidemiologíaRESUMEN
BACKGROUND: Interleukin-23 (IL-23) has been implicated in inflammatory and autoimmune diseases by skewing CD4+ T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL-23 receptor (IL-23R)-expressing cells in the atherosclerotic aorta and evaluated the effect of IL-23R deficiency on atherosclerosis development in mice. METHODS AND RESULTS: We used heterozygous Ldlr-/-Il23reGFP/WT knock-in mice to identify IL-23R-expressing cells by flow cytometry and homozygous Ldlr-/-Il23reGFP/eGFP (Ldlr-/-Il23r-/- ) mice to investigate the effect of lack of IL-23R in atherosclerosis. We demonstrate the presence of relatively rare IL-23R-expressing cells in lymphoid tissue and aorta (≈0.1-1% IL23R+ cells of all CD45+ leukocytes). After 10 weeks on a high-fat diet, production of IL-17, but not interferon-γ, by CD4+ T cells and other lymphocytes was reduced in Ldlr-/-Il23r-/- compared with Ldlr-/- controls. However, Ldlr-/- and Ldlr-/-Il23r-/- mice had equivalent amounts of aortic sinus and descending aorta lesions. Adoptive transfer of IL-23R-deficient CD4+ T cells to lymphopenic Ldlr-/-Rag1-/- resulted in dramatically reduced IL-17-producing T cells but did not reduce atherosclerosis, compared with transfer of IL-23R-sufficient CD4+ T cells. CONCLUSIONS: These data demonstrate that loss of IL-23R does not affect development of experimental atherosclerosis in LDLr-deficient mice, despite a role for IL-23 in differentiation of IL-17-producing T cells.
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Enfermedades de la Aorta/metabolismo , Receptores de Interleucina/deficiencia , Células Th17/metabolismo , Animales , Aorta Torácica/metabolismo , Aorta Torácica/patología , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/patología , Diferenciación Celular , Modelos Animales de Enfermedad , Citometría de Flujo , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Placa Aterosclerótica/inmunología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Receptores de Interleucina/biosíntesis , Células Th17/inmunologíaRESUMEN
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.
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Trampas Extracelulares/fisiología , Hidrolasas/fisiología , Placa Aterosclerótica/etiología , Trombosis/etiología , Animales , Trasplante de Médula Ósea , Enfermedades de las Arterias Carótidas/etiología , Enfermedades de las Arterias Carótidas/patología , Muerte Celular , Desoxirribonucleasa I/farmacología , Trampas Extracelulares/efectos de los fármacos , Humanos , Hidrolasas/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/fisiología , Osteomielitis/etiología , Placa Aterosclerótica/patología , Arginina Deiminasa Proteína-Tipo 4 , Trombosis/prevención & control , Túnica Íntima/lesionesRESUMEN
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.
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Aorta/metabolismo , Enfermedades de la Aorta/metabolismo , Aterosclerosis/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Células Th17/metabolismo , Traslado Adoptivo , Animales , Aorta/inmunología , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/patología , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/patología , Células Cultivadas , Colágeno/metabolismo , Modelos Animales de Enfermedad , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Factor 88 de Diferenciación Mieloide/deficiencia , Factor 88 de Diferenciación Mieloide/genética , Fenotipo , Placa Aterosclerótica , Receptores Tipo I de Interleucina-1/deficiencia , Receptores Tipo I de Interleucina-1/genética , Transducción de Señal , Células Th17/inmunología , Células Th17/trasplanteRESUMEN
The family of innate lymphoid cells (ILCs) consisting of NK cells, lymphoid tissue inducer cells and the 'helper'-like ILC subsets ILC1, ILC2 and ILC3 have been shown to have important roles in protection against microbes, regulation of inflammatory diseases and involved in allergic reactions. ILC1s produce IFN-γ upon stimulation with IL-12 and IL-18, ILC2s produce IL-5 and IL-13 responding to IL-33 and IL-25 while ILC3s produce IL-17 and IL-22 after stimulation with IL-23 or IL-1. Although few studies have directly investigated the role for ILCs in atherosclerosis, several studies have investigated transcription factors and cytokines shared by ILCs and T helper cells. In this review we summarize our current understanding of the role of ILC in atherosclerosis and discuss future directions.
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Aterosclerosis/inmunología , Inmunidad Innata , Linfocitos , Animales , Humanos , Linfocitos/citología , Linfocitos/inmunologíaRESUMEN
CD47 is known to play an important role in CD4+ T cell homeostasis. We recently reported a reduction in mice deficient in the Cd47 gene (Cd47-/-) CD4+ T cell adhesion and transendothelial migration (TEM) in vivo and in vitro as a result of impaired expression of high-affinity forms of LFA-1 and VLA-4 integrins. A prior study concluded that Cd47-/- mice were resistant to experimental autoimmune encephalomyelitis (EAE) as a result of complete failure in CD4+ T cell activation after myelin oligodendrocyte glycoprotein peptide 35-55 aa (MOG35-55) immunization. As the prior EAE study was published before our report, authors could not have accounted for defects in T cell integrin function as a mechanism to protect Cd47-/- in EAE. Thus, we hypothesized that failure of T cell activation involved defects in LFA-1 and VLA-4 integrins. We confirmed that Cd47-/- mice were resistant to MOG35-55-induced EAE. Our data, however, supported a different mechanism that was not a result of failure of CD4+ T cell activation. Instead, we found that CD4+ T cells in MOG35-55-immunized Cd47-/- mice were activated, but clonal expansion contracted within 72 h after immunization. We used TCR crosslinking and mitogen activation in vitro to investigate the underlying mechanism. We found that naïve Cd47-/- CD4+ T cells exhibited a premature block in proliferation and survival because of impaired activation of LFA-1, despite effective TCR-induced activation. These results identify CD47 as an important regulator of LFA-1 and VLA-4 integrin-adhesive functions in T cell proliferation, as well as recruitment, and clarify the roles played by CD47 in MOG35-55-induced EAE.
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Linfocitos T CD4-Positivos/inmunología , Antígeno CD47/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Traslado Adoptivo , Animales , Anticuerpos Monoclonales/farmacología , Presentación de Antígeno/efectos de los fármacos , Presentación de Antígeno/inmunología , Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimiocinas/farmacología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Inmunización , Integrina alfa4beta1/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
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.
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Aterosclerosis/inmunología , Células de la Médula Ósea/fisiología , Células Dendríticas/fisiología , Factores de Transcripción de Tipo Kruppel/metabolismo , Linfocitos T/inmunología , Animales , Trasplante de Médula Ósea , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Inmunidad Celular , Factores de Transcripción de Tipo Kruppel/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL/genéticaRESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales/toxicidad , Enfermedades de la Aorta/inducido químicamente , Aterosclerosis/inducido químicamente , Linfocitos T CD4-Positivos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Proteínas de la Membrana/antagonistas & inhibidores , Receptores de LDL/deficiencia , Animales , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Apoptosis/efectos de los fármacos , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Femenino , Receptor Celular 1 del Virus de la Hepatitis A , Lipoproteínas LDL/metabolismo , Activación de Linfocitos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Masculino , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Ratones Noqueados , Fagocitosis/efectos de los fármacos , Placa Aterosclerótica , Receptores de LDL/genética , Transducción de Señal/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunologíaRESUMEN
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.