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1.
Nat Med ; 25(10): 1576-1588, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591603

RESUMO

Atherosclerosis is driven by multifaceted contributions of the immune system within the circulation and at vascular focal sites. However, specific characteristics of dysregulated immune cells within atherosclerotic lesions that lead to clinical events such as ischemic stroke or myocardial infarction are poorly understood. Here, using single-cell proteomic and transcriptomic analyses, we uncovered distinct features of both T cells and macrophages in carotid artery plaques of patients with clinically symptomatic disease (recent stroke or transient ischemic attack) compared to asymptomatic disease (no recent stroke). Plaques from symptomatic patients were characterized by a distinct subset of CD4+ T cells and by T cells that were activated and differentiated. Moreover, some T cell subsets in these plaques presented markers of T cell exhaustion. Additionally, macrophages from these plaques contained alternatively activated phenotypes, including subsets associated with plaque vulnerability. In plaques from asymptomatic patients, T cells and macrophages were activated and displayed evidence of interleukin-1ß signaling. The identification of specific features of innate and adaptive immune cells in plaques that are associated with cerebrovascular events may enable the design of more precisely tailored cardiovascular immunotherapies.


Assuntos
Aterosclerose/imunologia , Interleucina-1beta/genética , Placa Aterosclerótica/metabolismo , Análise de Célula Única , Imunidade Adaptativa/genética , Idoso , Aterosclerose/genética , Aterosclerose/patologia , Diferenciação Celular/genética , Endarterectomia das Carótidas , Feminino , Humanos , Imunidade Inata/genética , Interleucina-1beta/imunologia , Leucócitos Mononucleares , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/patologia , Proteoma/genética , Proteoma/imunologia , Transdução de Sinais/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia
2.
Toxicol Lett ; 316: 27-34, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513887

RESUMO

OBJECTIVE: Atherosclerosis is an autoimmune inflammatory disease that is closely associated with long-term exposure to fine particulate matter (PM2.5). CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses, and the depletion of CD4+CD25+Foxp3+ Tregs has been thought to play a prominent role in atherosclerosis. Therefore, we investigated the association between the CD4+CD25+Foxp3+ Tregs population and atherosclerotic development in ApoE-/- mice exposed to PM2.5. METHODS: We employed a real-world system to subject 40 ApoE-/- mice to ambient inhalation of PM2.5 (PM2.5 group, n = 20) or filtered air (FA group, n = 20) for 12 weeks. PM2.5 source apportionment, atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum level of inflammatory factors and lipid profiles, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen were quantified, respectively. RESULTS: The daily average concentration of PM2.5 was 57.4 ± 25.6 µg/m3. Atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum levels of IL-6, TNF-α, TC and LDL-C in the PM2.5 group increased significantly compared to the FA group. Whereas, serum levels of IL-10 and TGF-ß, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen in the PM2.5 group decreased significantly compared to the FA group. CONCLUSION: These results suggest that PM2.5 could accelerate the development of atherosclerosis in ApoE-/- mice, which is related to CD4+CD25+Foxp3+ Tregs down-regulation, as well as lipid deposition and systemic inflammation.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/induzido quimicamente , Aterosclerose/induzido quimicamente , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Material Particulado/toxicidade , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/imunologia , Aterosclerose/patologia , Biomarcadores/sangue , LDL-Colesterol/sangue , Citocinas/sangue , Modelos Animais de Doenças , Progressão da Doença , Fatores de Transcrição Forkhead/imunologia , Predisposição Genética para Doença , Mediadores da Inflamação/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Tamanho da Partícula , Fenótipo , Placa Aterosclerótica , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fatores de Tempo
3.
Int J Oral Sci ; 11(3): 21, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257363

RESUMO

Growing evidence suggests close associations between periodontitis and atherosclerosis. To further understand the pathological relationships of these associations, we developed periodontitis with ligature placement around maxillary molars or ligature placement in conjunction with Porphyromonas gingivalis lipopolysaccharide injection at the ligature sites (ligature/P.g. LPS) in Apolipoprotein E knock out mice and studied the atherogenesis process in these animals. The mice were fed with high fat diet for 11 weeks and sacrificed for analyzing periodontitis, systemic inflammation, and atherosclerosis. Controls did not develop periodontitis or systemic inflammation and had minimal lipid deposition in the aortas, but mice receiving ligature or ligature/P.g. LPS showed severe periodontitis, systemic inflammation, and aortic plaque formation. The aortic plaque contained abundant macrophages and cells expressing both endothelial and mesenchymal cell markers. The severity of periodontitis was slightly higher in mice receiving ligature/P.g. LPS than ligature alone, and the magnitude of systemic inflammation and aortic plaque formation were also notably greater in the mice with ligature/P.g. LPS. These observations indicate that the development of atherosclerosis is due to systemic inflammation caused by severe periodontitis. In vitro, P.g. LPS enhanced the secretion of pro-inflammatory cytokines from macrophages and increased the adhesion of monocytes to endothelial cells by upregulating the expression of adhesion molecules from endothelial cells. Moreover, secretory proteins, such as TNF-α, from macrophages induced endothelial-mesenchymal transitions of the endothelial cells. Taken together, systemic inflammation induced by severe periodontitis might exacerbate atherosclerosis via, in part, causing aberrant functions of vascular endothelial cells and the activation of macrophages in mice.


Assuntos
Aterosclerose/imunologia , Inflamação , Periodontite/imunologia , Periodontite/fisiopatologia , Animais , Aterosclerose/patologia , Modelos Animais de Doenças , Células Endoteliais , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Periodontite/patologia , Porphyromonas gingivalis
4.
Immunohorizons ; 3(1): 37-44, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31356175

RESUMO

Depletion of B cells attenuates plaque development and modulates T cell responses in mouse models of atherosclerosis, suggesting that Ag presentation by B cells may promote disease progression. Thus, we set out to determine the role of B cell-mediated MHC class II (MHC II) Ag presentation during atherosclerotic plaque development. We developed murine conditional MHC II deletion and expression systems under control of the B cell-restricted CD19 promoter in an experimental model of atherosclerosis. Mice lacking MHC II expression only on B cells exhibited systemic shifts in germinal center and marginal zone B cell populations, leading to a reduced Ab response compared with littermate control animals. However, all populations were present and normal cholesterol uptake was detected in the plasma following high-fat diet treatment. In a second model, in which conditional expression of MHC II is limited only to B cells, showed similar overall cellularity characteristics compared with mice with complete MHC II deficiency. High-fat diet feeding showed no major changes in atherosclerotic plaque size or plaque cellular content in either conditional deletion or conditional expression approaches, compared with control animals. By testing the necessity and sufficiency of MHC II on B cells in the progression of atherosclerosis, we determine that MHC II on B cells does not directly regulate lesion development in murine models.


Assuntos
Apresentação do Antígeno/imunologia , Aterosclerose/imunologia , Linfócitos B/imunologia , Progressão da Doença , Antígenos de Histocompatibilidade Classe II/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Colesterol/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Antígenos de Histocompatibilidade Classe II/genética , Imunoglobulina G/sangue , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Placa Aterosclerótica/metabolismo , Receptores de IgG/sangue , Timo/transplante
5.
Mediators Inflamm ; 2019: 4128682, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205450

RESUMO

Vascular complications of diabetes mellitus represent a major public health problem. Although many steps forward have been made to define the causes and to find the best possible therapies, the problem remains crucial. In recent years, more and more evidences have defined a link between microbiota and the initiation, promotion, and evolution of atherosclerotic disease, even in the diabetic scenario. There is an urgency to develop the knowledge of modern medicine about the link between gut microbiota and its host's metabolic pathways, and it would be useful to understand and justify the interindividual diversity of clinical disease presentation of diabetic vascular complication even if an optimization of pharmacological treatment has been made or in the case of young patients where hypertension, dyslipidemia, and diabetes are not able to justify a very quick progress of atherosclerotic process. The aim of the present review is to gather all the best available evidence in this regard and to define a new role of the microbiota in this field, from biomarker to possible therapeutic target.


Assuntos
Angiopatias Diabéticas/metabolismo , Microbiota/fisiologia , Doença Arterial Periférica/metabolismo , Animais , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/microbiologia , Angiopatias Diabéticas/imunologia , Angiopatias Diabéticas/microbiologia , Humanos , Doença Arterial Periférica/imunologia , Doença Arterial Periférica/microbiologia
6.
BMB Rep ; 52(6): 360-372, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31186085

RESUMO

Macrophages play an essential role not only in mediating the first line of defense but also in maintaining tissue homeostasis. In response to extrinsic factors derived from a given tissue, macrophages activate different functional programs to produce polarized macrophage populations responsible for inducing inflammation against microbes, removing cellular debris, and tissue repair. However, accumulating evidence has revealed that macrophage polarization is pivotal in the pathophysiology of metabolic syndromes and cancer, as well as in infectious and autoimmune diseases. Recent advances in transcriptomic and metabolomic studies have highlighted the link between metabolic rewiring of macrophages and their functional plasticity. These findings imply that metabolic adaption to their surrounding microenvironment instructs activation of macrophages with functionally distinct phenotypes, which in turn probably leads to the pathogenesis of a wide spectrum of diseases. In this review, we have introduced emerging concepts in immunometabolism with focus on the impact on functional activation of macrophages. Furthermore, we have discussed the implication of macrophage plasticity on the pathogenesis of metabolic syndromes and cancer, and how the disease microenvironment manipulates macrophage metabolism with regard to the pathophysiology. [BMB Reports 2019; 52(6): 360-372].


Assuntos
Polaridade Celular/fisiologia , Macrófagos/citologia , Macrófagos/metabolismo , Aterosclerose/imunologia , Homeostase , Humanos , Imunomodulação/fisiologia , Inflamação/metabolismo , Ativação de Macrófagos/fisiologia , Neoplasias/imunologia , Obesidade/imunologia , Fenótipo
7.
PLoS One ; 14(5): e0215604, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31050669

RESUMO

AIM: Although the atheroprotective effects of statins and angiotensin II receptor blockers (ARBs) are well-established, little is known about their additive effects, especially during the early period of atherosclerosis. The aim of this study was to investigate whether combination of a statin and an ARB exerts synergistic anti-atherosclerotic effects, and to elucidate the mechanisms of combined effects. METHODS: Atherosclerotic plaques were developed in arteries of 23 rabbits using a high-cholesterol diet (HCD) and intra-arterial balloon inflation. Rabbits received one of five different treatment strategies for 4 weeks: positive control [n = 5, HCD]; negative control [n = 3, regular chow diet]; statin [n = 5, HCD and rosuvastatin 10 mg]; ARB [n = 5, HCD and olmesartan 20 mg]; and combination [n = 5, HCD and statin+ARB]. RESULTS: Histological analysis demonstrated that development of atherosclerotic plaques was inhibited more in combination group than in statin group (P = 0.001). Although macrophage infiltration identified by RAM11 staining was not significantly different between combination and individual treatment groups (31.76±4.84% [combination] vs. 38.11±6.53% [statin; P = 0.35] or 35.14±2.87% [ARB; P = 0.62]), the relative proportion of pro-inflammatory M1-macrophages was significantly lower in combination group than in ARB group (3.20±0.47% vs. 5.20±0.78%, P = 0.02). Furthermore, M2-macrophage polarization was higher in combination group than in statin group (17.70±3.04% vs. 7.86±0.68%, P = 0.001). CONCLUSION: Combination treatment with a statin and an ARB produced synergistic protective effects for atherosclerosis initiation and progression, which may be attributed to modulation of macrophage characteristics in the early period of atherosclerosis.


Assuntos
Antagonistas de Receptores de Angiotensina/administração & dosagem , Aterosclerose/tratamento farmacológico , Imidazóis/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem , Tetrazóis/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Aterosclerose/imunologia , Aterosclerose/prevenção & controle , Polaridade Celular , Modelos Animais de Doenças , Sinergismo Farmacológico , Imidazóis/farmacologia , Macrófagos/metabolismo , Masculino , Camundongos , Células RAW 264.7 , Coelhos , Rosuvastatina Cálcica/farmacologia , Tetrazóis/farmacologia , Resultado do Tratamento
8.
Int Immunopharmacol ; 73: 146-155, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100709

RESUMO

Activation of NOD-like receptor (NLR) family and pyrin domain containing 3 (NLRP3) inflammasome contributes to inflammation and may lead to atherosclerosis. The NLRP3 inflammasome as a molecular platform regulates the activation of ATP signaling, K+ efflux, cathepsin-B activity, lysosomal function and pro-inflammatory cytokines (i.e. IL-1ß and IL-18). Statins has been widely prescribed for the treatment of hyperlipidemia and cardiovascular diseases. In addition to lipid-lowering effect, statins have immunomodulatory, anti-inflammatory, antioxidant and antiapoptotic functions. An increasing number of studies indicated NLRP3 inflammasome and their downstream mediators as important targets for statin drugs in inflammatory diseases. In this review, we discussed different aspect of the NLRP3 inflammasome signaling pathways and focused on the effect of statin drugs on NLRP3 inflammasomes in association to atherosclerosis in order to elucidate possible targets for future research and clinical settings.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Humanos
9.
Immunity ; 50(5): 1132-1148, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117010

RESUMO

Helping B cells and antibody responses is a major function of CD4+ T cells. It has been 10 years since the publication of Bcl6 as the lineage-defining transcription factor for T follicular helper (Tfh) differentiation and the requirement of Tfh cells as the specialized subset of CD4+ T cells needed for germinal centers (the microanatomical sites of B cell mutation and antibody affinity maturation) and related B cell responses. A great deal has been learned about Tfh cells in the past 10 years, particularly regarding their roles in a surprising range of diseases. Advances in the understanding of Tfh cell differentiation and function are discussed, as are the understanding of Tfh cells in infectious diseases, vaccines, autoimmune diseases, allergies, atherosclerosis, organ transplants, and cancer. This includes discussion of Tfh cells in the human immune system. Based on the discoveries to date, the next decade of Tfh research surely holds many more surprises. VIDEO ABSTRACT.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Aterosclerose/imunologia , Doenças Autoimunes/imunologia , Diferenciação Celular/imunologia , Doenças Transmissíveis/imunologia , Humanos , Hipersensibilidade/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo
10.
Immunopharmacol Immunotoxicol ; 41(3): 446-454, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31124391

RESUMO

Context: Atherosclerosis is a chronic inflammatory disease in which the plaques were built up inside of the artery. Interleukin-8 (IL-8, CXCL8) is an inflammatory factor, known to play an important role in the development of atherosclerosis. G31P is an antagonist of the IL-8 receptor, which plays roles in vascular smooth muscle cell (VSMC) proliferation and migration. Objective: This study is to investigate the therapeutic effect of G31P on atherosclerosis through a mouse model. Materials and methods: A mouse model of atherosclerosis was generated through feeding the ApoE-/- mice with high fat diet for 12 weeks. G31P was injected subcutaneously into the mice. The levels of keratinocyte chemoattractant (KC), CXCR2, TNF-α, and IFN-γ were analyzed through ELISA. The expressions of MMP-2, MMP-9, PCNA, and Mef2a in aortic tissues were detected through RT-qPCR. In A7r5 cells, the levels of p-ERK, ROCK1, and ROCK2 were analyzed by western blot. Intracellular calcium levels were measured through Fluo-3 AM assay. Results and disccussion: G31P suppressed the abnormal lipid profile and decreased the levels of KC, MMP-2, MMP-9, PCNA, and Mef2a in a mouse model of atherosclerosis. In addition, G31P also inhibited the expressions of p-ERK, ROCK1, ROCK2, and decreased the calcium concentrations in A7r5 cells. Conclusions: These findings indicate the potential therapeutic effects of G31P in suppressing the development of atherosclerosis by antagonizing the IL-8 receptor. G31P inhibits the proliferation and migration of VSMCs through regulating the Rho-kinase, ERK, and calcium-dependent pathways.


Assuntos
Aorta/imunologia , Aterosclerose/tratamento farmacológico , Interleucina-8/farmacologia , Músculo Liso Vascular/imunologia , Miócitos de Músculo Liso/imunologia , Fragmentos de Peptídeos/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Animais , Aorta/patologia , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/imunologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Camundongos , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/patologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/imunologia , Quinases Associadas a rho/genética , Quinases Associadas a rho/imunologia
11.
Mediators Inflamm ; 2019: 7434376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089324

RESUMO

Atherosclerosis is one of the leading causes of death and disability worldwide. It is a complex disease characterized by lipid accumulation within the arterial wall, inflammation, local neoangiogenesis, and apoptosis. Innate immune effectors, in particular monocytes and macrophages, play a pivotal role in atherosclerosis initiation and progression. Although most of available evidence on the role of monocytes and macrophages in atherosclerosis is derived from animal studies, a growing body of evidence elucidating the role of these mononuclear cell subtypes in human atherosclerosis is currently accumulating. A novel pathogenic role of monocytes and macrophages in terms of atherosclerosis initiation and progression, in particular concerning the role of these cell subsets in neovascularization, has been discovered. The aim of the present article is to review currently available evidence on the role of monocytes and macrophages in human atherosclerosis and in relation to plaque characteristics, such as plaque neoangiogenesis, and patients' prognosis and their potential role as biomarkers.


Assuntos
Aterosclerose/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Placa Aterosclerótica/metabolismo , Animais , Aterosclerose/imunologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Placa Aterosclerótica/imunologia
12.
Int J Mol Sci ; 20(10)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137759

RESUMO

The concept of „trained innate immunity" is understood as the ability of innate immune cells to remember invading agents and to respond nonspecifically to reinfection with increased strength. Trained immunity is orchestrated by epigenetic modifications leading to changes in gene expression and cell physiology. Although this phenomenon was originally seen mainly as a beneficial effect, since it confers broad immunological protection, enhanced immune response of reprogrammed innate immune cells might result in the development or persistence of chronic metabolic, autoimmune or neuroinfalmmatory disorders. This paper overviews several examples where the induction of trained immunity may be essential in the development of diseases characterized by flawed innate immune response.


Assuntos
Aterosclerose/imunologia , Diabetes Mellitus/imunologia , Imunidade Inata , Memória Imunológica , Doenças Neurodegenerativas/imunologia , Animais , Humanos
13.
Mediators Inflamm ; 2019: 3152040, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093011

RESUMO

Interleukin- (IL-) 35, a novel functional cytokine of regulatory T cells (Treg) comprised of the IL-12p35 subunit and the other subunit Epstein-Barr virus-induced gene 3 (EBI3), regulates the activity of CD4+ T cells and macrophages, thereby playing a critical role in inflammatory and autoimmune diseases. Previous studies demonstrated that both recombinant mice and human IL-35 attenuated atherosclerosis in ApoE-/- mice. Additionally, EBI3 deficiency enhanced the activation of macrophages and increased atherosclerotic lesions in LDLR-/- mice. This study generated double-deficient mice for ApoE and IL-12p35 (ApoE-/- IL-12p35-/- mice) and investigated the effect of IL-12p35 deficiency on atherosclerosis. IL-12p35 deficiency alleviated Th1/Th2 imbalance, aggravated Th17/Treg imbalance, and attenuated atherosclerotic plaque formation in ApoE-/- mice. Additionally, exogenous rIL-35 treatment reversed the imbalance of Th17/Treg and attenuated atherosclerosis in ApoE-/- mice. These findings suggest that IL-12p35 deficiency ameliorates atherosclerosis in ApoE-/- mice, partially, via attenuating the Th1/Th2 imbalance, although IL-12p35 deficiency aggravates the Th17/Treg imbalance.


Assuntos
Subunidade p35 da Interleucina-12/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo , Animais , Apolipoproteínas E , Aterosclerose/imunologia , Aterosclerose/metabolismo , Imuno-Histoquímica , Interleucina-10/metabolismo , Subunidade p35 da Interleucina-12/deficiência , Interleucina-4/metabolismo , Masculino , Camundongos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo
14.
Philos Trans R Soc Lond B Biol Sci ; 374(1765): 20180147, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30967001

RESUMO

Macrophages respond to several stimuli by forming florid membrane ruffles that lead to fluid uptake by macropinocytosis. This type of induced macropinocytosis, executed by a variety of non-malignant and malignant cells, is initiated by transmembrane receptors and is involved in nutrient acquisition and mTOR signalling. However, macrophages also perform a unique type of constitutive ruffling and macropinocytosis that is dependent on the presence of extracellular calcium. Calcium-sensing receptors are responsible for this activity. This distinct form of macropinocytosis enables macrophages to continuously sample their microenvironment for antigenic molecules and for pathogen- and danger-associated molecular patterns, as part of their immune surveillance functions. Interestingly, even within the monocyte lineage, there are differences in macropinocytic ability that reflect the polarized functional roles of distinct macrophage subsets. This review discusses the shared and distinct features of both induced and constitutive macropinocytosis displayed by the macrophage lineage and their roles in physiology, immunity and pathophysiology. In particular, we analyse the role of macropinocytosis in the uptake of modified low-density lipoprotein (LDL) and its contribution to foam cell and atherosclerotic plaque formation. We propose a combined role of scavenger receptors and constitutive macropinocytosis in oxidized LDL uptake, a process we have termed 'receptor-assisted macropinocytosis'. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.


Assuntos
Aterosclerose/etiologia , Imunidade/fisiologia , Macrófagos/fisiologia , Pinocitose/fisiologia , Animais , Aterosclerose/imunologia , Aterosclerose/fisiopatologia , Humanos
15.
Nat Commun ; 10(1): 1801, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30996248

RESUMO

Macrophage-orchestrated, low-grade chronic inflammation plays a pivotal role in obesity and atherogenesis. However, the underlying regulatory mechanisms remain incompletely understood. Here, we identify major vault protein (MVP), the main component of unique cellular ribonucleoprotein particles, as a suppressor for NF-κB signaling in macrophages. Both global and myeloid-specific MVP gene knockout aggravates high-fat diet induced obesity, insulin resistance, hepatic steatosis and atherosclerosis in mice. The exacerbated metabolic disorders caused by MVP deficiency are accompanied with increased macrophage infiltration and heightened inflammatory responses in the microenvironments. In vitro studies reveal that MVP interacts with TRAF6 preventing its recruitment to IRAK1 and subsequent oligomerization and ubiquitination. Overexpression of MVP and its α-helical domain inhibits the activity of TRAF6 and suppresses macrophage inflammation. Our results demonstrate that macrophage MVP constitutes a key constraint of NF-κB signaling thereby suppressing metabolic diseases.


Assuntos
Aterosclerose/imunologia , Fígado Gorduroso/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Obesidade/imunologia , Partículas de Ribonucleoproteínas em Forma de Abóbada/metabolismo , Tecido Adiposo/patologia , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Biópsia , Células da Medula Óssea , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Feminino , Técnicas de Inativação de Genes , Humanos , Quinase I-kappa B/metabolismo , Inflamação/etiologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Cultura Primária de Células , Transdução de Sinais/imunologia , Fator 6 Associado a Receptor de TNF/metabolismo , Ubiquitinação , Partículas de Ribonucleoproteínas em Forma de Abóbada/genética , Partículas de Ribonucleoproteínas em Forma de Abóbada/imunologia
16.
Immunity ; 50(4): 941-954, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995508

RESUMO

Arterial inflammation is a hallmark of atherosclerosis, and appropriate management of this inflammation represents a major unmet therapeutic need for cardiovascular disease patients. Here, we review the diverse contributions of immune cells to atherosclerosis, the mechanisms of immune cell activation in this context, and the cytokine circuits that underlie disease progression. We discuss the recent application of these insights in the form of immunotherapy to treat cardiovascular disease and highlight how studies on the cardiovascular co-morbidity that arises in autoimmunity might reveal additional roles for cytokines in atherosclerosis. Currently, data point to interleukin-1ß (IL-1ß), tumor necrosis factor (TNF), and IL-17 as cytokines that, at least in some settings, are effective targets to reduce cardiovascular disease progression.


Assuntos
Doenças Cardiovasculares/imunologia , Citocinas/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Cardiovasculares/tratamento farmacológico , Colesterol/metabolismo , Ensaios Clínicos como Assunto , Citocinas/antagonistas & inibidores , Citocinas/uso terapêutico , Progressão da Doença , Células Espumosas/imunologia , Células Espumosas/metabolismo , Microbioma Gastrointestinal , Humanos , Inflamassomos/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-1beta/antagonistas & inibidores , Camundongos Knockout , Modelos Imunológicos , Músculo Liso Vascular/imunologia , Fagócitos/imunologia , Fagócitos/metabolismo , Transdução de Sinais , Suínos , Pesquisa Médica Translacional
17.
Scand J Immunol ; 90(1): e12766, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30929259

RESUMO

BACKGROUND: Signal regulatory protein alpha (SIRPa) is an essential signalling molecule that modulates inflammatory responses in macrophages. However, the regulation of SIRPs and its dynamic changes in macrophages under inflammatory stimulation in atherosclerosis remain uncertain. OBJECTIVE: The study aimed to identify the miRNAs that regulate SIRPa transcription and their roles in modulating phagocytosis, differentiation and cholesterol efflux in macrophages. METHODS: ApoE knockout mice were fed with a high-fat diet for 12 weeks. Intimal lesion areas and lipid accumulation were assessed by haematoxylin and eosin (HE) and oil red O staining. The expression of mRNAs/miRNAs was assessed by RNA-seq (RNA sequencing) and RT-qPCR (real-time quantitative polymerase chain reaction). The identification of miR-378a associated with SIRPa regulation in macrophages induced by ox-LDL was confirmed by RT-qPCR and Western blot. The phagocytosis and differentiation of macrophages were detected to figure out the role of miR-378a and SIRPa. RESULTS: SIRPa was proved to be a target of miR-378a. Reduced miR-378a can promote the expression of SIRPa. RNA-seq data showed that the levels of mRNA associated with macrophage phenotypes and SIRPa-CD47 axis were increasing significantly with a decreasing phagocytic phenotype in ApoE-/- mice vs wild-type (WT) mice (P < 0.01). The level of miR-378a was reduced in the aorta of ApoE-/- mice vs WT mice. The experiment in vitro showed that overexpression of miR-378a in macrophages decreased the level of Sirpa mRNA obviously vs control (P < 0.01). The phagocytic activity of miR-378a-transfected macrophages was promoted vs control (P < 0.05). miR-378a significantly depleted Sirpa levels in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages (P < 0.05), and depletion of miR-378a reversed Sirpa reduction obviously (P < 0.05). miR-378a promoted the secretion of TNF-a and IL-6 indirectly. CONCLUSION: It has been demonstrated that miR-378a regulates SIRPa-mediated phagocytosis and polarization of macrophages by a direct or indirect way. This research may provide a new path to promote reverse cholesterol transport of macrophages and hinder the progress of atherosclerosis.


Assuntos
Aterosclerose/genética , Inflamação/genética , Macrófagos/fisiologia , MicroRNAs/genética , Animais , Aterosclerose/imunologia , Antígeno CD47/genética , Diferenciação Celular , Células Cultivadas , Colesterol/metabolismo , Dieta Hiperlipídica , Humanos , Inflamação/imunologia , Camundongos , Camundongos Knockout para ApoE , Fagocitose/genética , Receptores Imunológicos/genética , Transdução de Sinais
18.
Am J Med ; 132(3): 312-324, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30832770

RESUMO

Inflammation has proven in multiple studies to be responsible for the progression of cardiometabolic diseases and malignancies. The interleukin family has been critically associated with progression of atherosclerosis, insulin resistance, and various malignancies. Given the advent of pharmacologic interleukin-1 (IL-1) inhibition, this pathway can potentially be targeted to improve outcomes. In the recently concluded Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial, investigators looked at the potential role of IL-1 (especially IL-1ß) inhibition in halting the progression of atherosclerosis. In the subset analysis of the data from this trial, IL-1ß inhibition with canakinumab was found to have beneficial effects in other cardiometabolic diseases characterized by inflammation, like diabetes, stroke, and chronic kidney disease, and also in patients with lung cancer. In this article, we will try to review the current literature on the role of canakinumab in the treatment of cardiometabolic diseases and malignancies.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Síndrome Metabólica/tratamento farmacológico , Neoplasias/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Doenças Cardiovasculares/imunologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/imunologia , Humanos , Síndrome Metabólica/imunologia , Neoplasias/imunologia , Neoplasias/prevenção & controle , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/imunologia
20.
Herz ; 44(2): 107-120, 2019 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-30859253

RESUMO

There is now overwhelming experimental and clinical evidence that arteriosclerosis is a chronic inflammatory disease. Lessons learned from genome-wide association studies, advanced in vivo imaging techniques, transgenic lineage tracing mice models and clinical interventional studies have shown that both innate and adaptive immune mechanisms can accelerate or curb arteriosclerosis. This article summarizes and discusses the pathogenesis of arteriosclerosis with a focus on the role of the adaptive immune system. Some limitations of animal models are discussed and the need for models that are tailored to better translate to human atherosclerosis and ultimately progress in prevention and treatment are emphasized.


Assuntos
Aterosclerose , Inflamação , Animais , Aterosclerose/imunologia , Estudo de Associação Genômica Ampla , Humanos , Camundongos
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