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1.
Nat Cardiovasc Res ; 3: 269-282, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38974464

ABSTRACT

Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, and its main complications, myocardial infarction and stroke, are the leading cause of mortality worldwide [1], [2]. Recent studies have identified Triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating myeloid cell functions [3], to be highly expressed in macrophage foam cells in experimental and human atherosclerosis [4]. However, the role of TREM2 in atherosclerosis is not fully known. Here, we show that hematopoietic or global TREM2 deficiency increased, whereas TREM2 agonism decreased necrotic core formation in early atherosclerosis. We demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages, and to the survival of lipid-laden macrophages, indicating a crucial role of TREM2 in maintaining the balance between foam cell death and clearance of dead cells in atherosclerotic lesions, thereby controlling plaque necrosis.

2.
Cardiovasc Res ; 120(3): 318-328, 2024 03 14.
Article in English | MEDLINE | ID: mdl-38381113

ABSTRACT

AIMS: The adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of 'poorly differentiated' T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis through the production of class-switched high-affinity antibodies. We therefore investigated the direct role of Tfh cells and the role of IL18 in Tfh differentiation in atherosclerosis. METHODS AND RESULTS: We generated atherosclerotic mouse models with selective genetic deletion of Tfh cells, MZB cells, or IL18 signalling in Tfh cells. Surprisingly, mice lacking Tfh cells had increased atherosclerosis. Lack of Tfh not only reduced class-switched IgG antibodies against oxidation-specific epitopes (OSEs) but also reduced atheroprotective natural IgM-type anti-phosphorylcholine (PC) antibodies, despite no alteration of natural B1 cells. Moreover, the absence of Tfh cells was associated with an accumulation of MZB cells with substantially reduced ability to secrete antibodies. In the same manner, MZB cell deficiency in Ldlr-/- mice was associated with a significant decrease in atheroprotective IgM antibodies, including natural anti-PC IgM antibodies. In humans, we found a positive correlation between circulating MZB-like cells and anti-OSE IgM antibodies. Finally, we identified an important role for IL18 signalling in HF/HC diet-induced Tfh. CONCLUSION: Our findings reveal a previously unsuspected role of MZB cells in regulating atheroprotective 'natural' IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications.


Subject(s)
Atherosclerosis , Interleukin-18 , Humans , Mice , Animals , Immunoglobulin M , B-Lymphocytes , Atherosclerosis/genetics , Atherosclerosis/prevention & control , Cholesterol , T-Lymphocytes, Helper-Inducer
3.
Immunity ; 56(8): 1809-1824.e10, 2023 08 08.
Article in English | MEDLINE | ID: mdl-37499656

ABSTRACT

Complement factor H (CFH) negatively regulates consumption of complement component 3 (C3), thereby restricting complement activation. Genetic variants in CFH predispose to chronic inflammatory disease. Here, we examined the impact of CFH on atherosclerosis development. In a mouse model of atherosclerosis, CFH deficiency limited plaque necrosis in a C3-dependent manner. Deletion of CFH in monocyte-derived inflammatory macrophages propagated uncontrolled cell-autonomous C3 consumption without downstream C5 activation and heightened efferocytotic capacity. Among leukocytes, Cfh expression was restricted to monocytes and macrophages, increased during inflammation, and coincided with the accumulation of intracellular C3. Macrophage-derived CFH was sufficient to dampen resolution of inflammation, and hematopoietic deletion of CFH in atherosclerosis-prone mice promoted lesional efferocytosis and reduced plaque size. Furthermore, we identified monocyte-derived inflammatory macrophages expressing C3 and CFH in human atherosclerotic plaques. Our findings reveal a regulatory axis wherein CFH controls intracellular C3 levels of macrophages in a cell-autonomous manner, evidencing the importance of on-site complement regulation in the pathogenesis of inflammatory diseases.


Subject(s)
Atherosclerosis , Complement C3 , Animals , Humans , Mice , Atherosclerosis/metabolism , Complement C3/genetics , Complement C3/metabolism , Complement Factor H/genetics , Complement Factor H/metabolism , Inflammation , Macrophages/metabolism
4.
J Clin Pathol ; 76(11): 770-777, 2023 Nov.
Article in English | MEDLINE | ID: mdl-36041815

ABSTRACT

BACKGROUND: Serological tests are widely used in various medical disciplines for diagnostic and monitoring purposes. Unfortunately, the sensitivity and specificity of test systems are often poor, leaving room for false-positive and false-negative results. However, conventional methods were used to increase specificity and decrease sensitivity and vice versa. Using SARS-CoV-2 serology as an example, we propose here a novel testing strategy: the 'sensitivity improved two-test' or 'SIT²' algorithm. METHODS: SIT² involves confirmatory retesting of samples with results falling in a predefined retesting zone of an initial screening test, with adjusted cut-offs to increase sensitivity. We verified and compared the performance of SIT² to single tests and orthogonal testing (OTA) in an Austrian cohort (1117 negative, 64 post-COVID-positive samples) and validated the algorithm in an independent British cohort (976 negatives and 536 positives). RESULTS: The specificity of SIT² was superior to single tests and non-inferior to OTA. The sensitivity was maintained or even improved using SIT² when compared with single tests or OTA. SIT² allowed correct identification of infected individuals even when a live virus neutralisation assay could not detect antibodies. Compared with single testing or OTA, SIT² significantly reduced total test errors to 0.46% (0.24-0.65) or 1.60% (0.94-2.38) at both 5% or 20% seroprevalence. CONCLUSION: For SARS-CoV-2 serology, SIT² proved to be the best diagnostic choice at both 5% and 20% seroprevalence in all tested scenarios. It is an easy to apply algorithm and can potentially be helpful for the serology of other infectious diseases.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/diagnosis , Seroepidemiologic Studies , Clinical Laboratory Techniques/methods , COVID-19 Testing , Sensitivity and Specificity
5.
Biomedicines ; 10(2)2022 Jan 20.
Article in English | MEDLINE | ID: mdl-35203427

ABSTRACT

Neutrophil extracellular traps (NETs) are DNA-protein structures released by neutrophils in response to various stimuli, including oxidized, low-density lipoprotein (oxLDL). Accumulating evidence suggests a role for NETs in the pathogenesis of abdominal aortic aneurysm (AAA). In this study, we investigated the potential association of lipoprotein particles and NETs in AAA in comparison to non-AAA control groups. The concentrations of neutrophil myeloperoxidase (MPO), the NET parameters citrullinated histone H3 (citH3) and circulating cell-free DNA (cfDNA), as well as of blood lipids were determined in plasma or serum of patients with AAA (n = 40), peripheral artery occlusive disease (PAD; n = 40) and healthy donors (n = 29). A sandwich ELISA detecting oxidized phosphatidylcholine in association with apolipoprotein B-100 (oxPL/apoB) was applied to measure oxidized phospholipids in circulation. The effect of lipoparticles on NET formation was tested using a DNA release assay with isolated human neutrophils. Plasma MPO, citH3 and cfDNA levels were significantly increased in AAA patients in comparison to healthy donors and PAD patients. Plasma concentrations of citH3 positively correlated with serum oxPL/apoB in AAA patients. In functional in vitro assays, the addition of oxLDL induced NET formation in pre-stimulated neutrophils. In conclusion, our data suggest a promoting role of oxLDL on NET formation in AAA patients.

6.
Nature ; 597(7874): 92-96, 2021 09.
Article in English | MEDLINE | ID: mdl-34433968

ABSTRACT

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide1. The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs)2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall2. A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs3, but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis.


Subject(s)
Atherosclerosis/metabolism , Atherosclerosis/prevention & control , Heparan Sulfate Proteoglycans/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism , Animals , B-Cell Maturation Antigen/metabolism , Binding Sites , Cardiovascular Diseases/blood , Cardiovascular Diseases/mortality , Female , Humans , Male , Mice , Mice, Inbred C57BL , Protein Binding , Transmembrane Activator and CAML Interactor Protein/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/blood , Tumor Necrosis Factor Ligand Superfamily Member 13/deficiency
8.
Front Immunol ; 11: 570963, 2020.
Article in English | MEDLINE | ID: mdl-33162986

ABSTRACT

The inhibitory immunoreceptor SIRPα is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRPα interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRPα on B1 lymphocytes, a subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRPα signaling (SIRPαΔCYT mice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective, we investigated the involvement of SIRPα signaling in atherosclerosis development. Bone marrow (SIRPαΔCYT>LDLR-/-) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRPα as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRPα as a potential therapeutic target in atherosclerosis.


Subject(s)
Atherosclerosis/immunology , B-Lymphocytes/immunology , CD47 Antigen/metabolism , Lymphoid Tissue/immunology , Receptors, Immunologic/metabolism , Animals , Antibody Formation , Autoantibodies/metabolism , Cell Movement , Cells, Cultured , Cytokines/metabolism , Immunomodulation , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Immunologic/genetics , Receptors, LDL/genetics , Th1 Cells/immunology , Transplantation Chimera
9.
Biology (Basel) ; 9(11)2020 Oct 22.
Article in English | MEDLINE | ID: mdl-33105582

ABSTRACT

In mice vaccination with Streptococcus pneumoniae results in an increase in anti-oxLDL IgM antibodies due to mimicry of anti-phosphorylcholine (present in the cell wall of S. pneumoniae) and anti-oxLDL IgM. In this study we investigated the human translation of this molecular mimicry by vaccination against S. pneumoniae using the Prevenar-13 vaccine. Twenty-four healthy male volunteers were vaccinated with Prevenar-13, either three times, twice or once in a double-blind, placebo-controlled, randomized single center clinical study. Anti-pneumococcal wall, oxLDL and phosphorycholine antibody levels were measured at a fixed serum dilution, as well as circulating lipid levels over the course of 68 weeks. A significant increase in anti-oxLDL IgG and IgM was seen in the group receiving two doses six months apart compared to the placebo. However, these differences were not observed in the groups receiving a single dose, two doses one month apart, or three doses. This study shows that vaccination with Prevenar-13 does not result in robust anti-oxLDL IgM levels in humans. Further research would be required to test alternative pneumococcal-based vaccines, vaccination regimens or study populations, such as cardiovascular disease patients.

10.
Proc Natl Acad Sci U S A ; 117(18): 9942-9951, 2020 05 05.
Article in English | MEDLINE | ID: mdl-32321835

ABSTRACT

Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like protein 1 (FHL-1) to self-ligands or altered self-ligands (e.g., malondialdehyde [MDA]-modified molecules) involved in homeostasis, thereby causing impaired complement regulation. Considering the critical role of CFH in inhibiting alternative pathway activation on MDA-modified surfaces, we performed an unbiased genome-wide search for genetic variants that modify the ability of plasma CFH to bind MDA in 1,830 individuals and characterized the mechanistic basis and the functional consequences of this. In a cohort of healthy individuals, we identified rs1061170 in CFH and the deletion of CFHR3 and CFHR1 as dominant genetic variants that modify CFH/FHL-1 binding to MDA. We further demonstrated that FHR1 and FHR3 compete with CFH for binding to MDA-epitopes and that FHR1 displays the highest affinity toward MDA-epitopes compared to CFH and FHR3. Moreover, FHR1 bound to MDA-rich areas on necrotic cells and prevented CFH from mediating its cofactor activity on MDA-modified surfaces, resulting in enhanced complement activation. These findings provide a mechanistic explanation as to why the deletion of CFHR3 and CFHR1 is protective in AMD and highlight the importance of genetic variants within the CFH/CFHR3/CFHR1 locus in the recognition of altered-self in tissue homeostasis.


Subject(s)
Blood Proteins/genetics , Complement C3b Inactivator Proteins/genetics , Macular Degeneration/genetics , Aged , Complement Factor H/genetics , Epitopes/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Macular Degeneration/pathology , Male , Malondialdehyde/metabolism , Middle Aged , Polymorphism, Single Nucleotide/genetics , Protein Binding
11.
Immunity ; 51(6): 1074-1087.e9, 2019 12 17.
Article in English | MEDLINE | ID: mdl-31784108

ABSTRACT

Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8+ T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation. VIDEO ABSTRACT.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Interferon Type I/immunology , Liver/metabolism , Lymphocytic choriomeningitis virus/immunology , Receptor, Interferon alpha-beta/metabolism , Animals , Arginine/blood , Cell Line , Chlorocebus aethiops , Cricetinae , Female , Hepatocytes/metabolism , Liver/immunology , Liver/virology , Lymphocytic Choriomeningitis/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Ornithine/blood , Ornithine Carbamoyltransferase/genetics , Signal Transduction/immunology , Urea/metabolism , Vero Cells
12.
Circ Res ; 125(11): 1019-1034, 2019 11 08.
Article in English | MEDLINE | ID: mdl-31610723

ABSTRACT

RATIONALE: Atherosclerosis is a chronic inflammatory disease. Recent studies have shown that dysfunctional autophagy in endothelial cells, smooth muscle cells, and macrophages, plays a detrimental role during atherogenesis, leading to the suggestion that autophagy-stimulating approaches may provide benefit. OBJECTIVE: Dendritic cells (DCs) are at the crossroad of innate and adaptive immune responses and profoundly modulate the development of atherosclerosis. Intriguingly, the role of autophagy in DC function during atherosclerosis and how the autophagy process would impact disease development has not been addressed. METHODS AND RESULTS: Here, we show that the autophagic flux in atherosclerosis-susceptible Ldlr-/- (low-density lipoprotein receptor-deficient) mice is substantially higher in splenic and aortic DCs compared with macrophages and is further activated under hypercholesterolemic conditions. RNA sequencing and functional studies on selective cell populations reveal that disruption of autophagy through deletion of Atg16l1 differentially affects the biology and functions of DC subsets in Ldlr-/- mice under high-fat diet. Atg16l1 deficient CD11b+ DCs develop a TGF (transforming growth factor)-ß-dependent tolerogenic phenotype and promote the expansion of regulatory T cells, whereas no such effects are seen with Atg16l1 deficient CD8α+ DCs. Atg16l1 deletion in DCs (all CD11c-expressing cells) expands aortic regulatory T cells in vivo, limits the accumulation of T helper cells type 1, and reduces the development of atherosclerosis in Ldlr-/- mice. In contrast, no such effects are seen when Atg16l1 is deleted selectively in conventional CD8α+ DCs and CD103+ DCs. Total T-cell or selective regulatory T-cell depletion abrogates the atheroprotective effect of Atg16l1 deficient DCs. CONCLUSIONS: In contrast to its proatherogenic role in macrophages, autophagy disruption in DCs induces a counter-regulatory response that maintains immune homeostasis in Ldlr-/- mice under high-fat diet and limits atherogenesis. Selective modulation of autophagy in DCs could constitute an interesting therapeutic target in atherosclerosis.


Subject(s)
Aorta/immunology , Aortic Diseases/prevention & control , Atherosclerosis/prevention & control , Autophagy , CD11b Antigen/immunology , Cell Communication , Cell Proliferation , Dendritic Cells/immunology , Lymphocyte Activation , T-Lymphocytes, Regulatory/immunology , Animals , Aorta/metabolism , Aorta/pathology , Aortic Diseases/immunology , Aortic Diseases/metabolism , Aortic Diseases/pathology , Atherosclerosis/immunology , Atherosclerosis/metabolism , Atherosclerosis/pathology , Autophagy-Related Protein 5/metabolism , Autophagy-Related Proteins/genetics , Autophagy-Related Proteins/metabolism , Bone Marrow Transplantation , CD11 Antigens/genetics , CD11 Antigens/metabolism , CD11b Antigen/metabolism , Cells, Cultured , Dendritic Cells/metabolism , Disease Models, Animal , Female , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Mice, Inbred C57BL , Mice, Knockout , Plaque, Atherosclerotic , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Receptors, LDL/genetics , Receptors, LDL/metabolism , Signal Transduction , T-Lymphocytes, Regulatory/metabolism
13.
Front Immunol ; 10: 1607, 2019.
Article in English | MEDLINE | ID: mdl-31354740

ABSTRACT

Complement factor H (CFH) has a pivotal role in regulating alternative complement activation through its ability to inhibit the cleavage of the central complement component C3, which links innate and humoral immunity. However, insights into the role of CFH in B cell biology are limited. Here, we demonstrate that deficiency of CFH in mice leads to altered splenic B cell development characterized by the accumulation of marginal zone (MZ) B cells. Furthermore, B cells in Cfh-/- mice exhibit enhanced B cell receptor (BCR) signaling as evaluated by increased levels of phosphorylated Bruton's tyrosine kinase (pBTK) and phosphorylated spleen tyrosine kinase (pSYK). We show that enhanced BCR activation is associated with uncontrolled C3 consumption in the spleen and elevated complement receptor 2 (CR2, also known as CD21) levels on the surface of mature splenic B cells. Moreover, aged Cfh-/- mice developed splenomegaly with distorted spleen architecture and spontaneous B cell-dependent autoimmunity characterized by germinal center hyperactivity and a marked increase in anti-double stranded DNA (dsDNA) antibodies. Taken together, our data indicate that CFH, through its function as a complement repressor, acts as a negative regulator of BCR signaling and limits autoimmunity.


Subject(s)
Autoantibodies/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Cell Differentiation/immunology , Complement Factor H/genetics , Spleen/immunology , Spleen/metabolism , Animals , Autoimmunity , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Biomarkers , Complement Factor H/deficiency , Complement Factor H/immunology , Immunophenotyping , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Mice , Mice, Knockout , Receptors, Antigen, B-Cell/metabolism , Signal Transduction
14.
Circulation ; 138(20): 2263-2273, 2018 11 13.
Article in English | MEDLINE | ID: mdl-29858401

ABSTRACT

BACKGROUND: Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell-activating factor (BAFF) receptor pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFF receptor ablates B-2 cells and decreases experimental atherosclerosis. Anti-BAFF immunotherapy is approved for treatment of autoimmune systemic lupus erythematosus, and can therefore be expected to limit their associated cardiovascular risk. However, direct effects of anti-BAFF immunotherapy on atherosclerosis remain unknown. METHODS: To investigate the effect of BAFF neutralization in atherosclerosis, the authors treated Apoe-/- and Ldlr-/- mice with a well-characterized blocking anti-BAFF antibody. Moreover, to investigate the mechanism by which BAFF impacts atherosclerosis, the authors studied atherosclerosis-prone mice that lack the alternative receptor for BAFF: transmembrane activator and calcium modulator and cyclophilin ligand interactor. RESULTS: The authors demonstrate here that anti-BAFF antibody treatment increased atherosclerosis in mice, despite efficient depletion of mature B-2 cells, suggesting a unique mechanism of action. Indeed, myeloid cell-specific deletion of transmembrane activator and calcium modulator and cyclophilin ligand interactor also results in increased atherosclerosis, while B cell-specific transmembrane activator and calcium modulator and cyclophilin ligand interactor deletion had no effect. Mechanistically, BAFF-transmembrane activator and calcium modulator and cyclophilin ligand interactor signaling represses macrophage IRF7-dependent (but not NF-κB-dependent) Toll-like receptor 9 responses including proatherogenic CXCL10 production. CONCLUSIONS: These data identify a novel B cell-independent anti-inflammatory role for BAFF in atherosclerosis and may have important clinical implications.


Subject(s)
Antibodies/therapeutic use , Atherosclerosis/therapy , B-Cell Activating Factor/immunology , Animals , Antibodies/immunology , Aorta/pathology , Bone Marrow Cells/cytology , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Chemokine CXCL10/genetics , Chemokine CXCL10/metabolism , Cholesterol/blood , Immunotherapy , Interferon Regulatory Factor-7/metabolism , Macrophages/cytology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Toll-Like Receptor 9/metabolism , Transmembrane Activator and CAML Interactor Protein/genetics , Transmembrane Activator and CAML Interactor Protein/metabolism
15.
Circ Res ; 122(6): 813-820, 2018 03 16.
Article in English | MEDLINE | ID: mdl-29436389

ABSTRACT

RATIONALE: Despite an established role for adaptive immune responses in atherosclerosis, the contribution of dendritic cells (DCs) and their various subsets is still poorly understood. OBJECTIVE: Here, we address the role of IRF8 (interferon regulatory factor 8)-dependent DCs (lymphoid CD8α+ and their developmentally related nonlymphoid CD103+ DCs) in the induction of proatherogenic immune responses during high fat feeding. METHODS AND RESULTS: Using a fate-mapping technique to track DCs originating from a DNGR1+ (dendritic cell natural killer lectin group receptor 1) precursor (Clec9a+/creRosa+/EYFP mice), we first show that YFPhiCD11chiMHCIIhi (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor-deficient (Ldlr-/-) mice and are CD11b-CD103+IRF8hi. Restricted deletion of IRF8 in DCs (Irf8flox/floxCd11cCre ) reduces the accumulation of CD11chiMHCIIhi DCs in the aorta without affecting CD11b+CD103- DCs or macrophages but completely abolishes the accumulation of aortic CD11b-CD103+ DCs. Lymphoid CD8α+ DCs are also deleted. This is associated with a significant reduction of aortic T-cell accumulation and a marked reduction of high-fat diet-induced systemic T-cell priming, activation, and differentiation toward T helper type 1 cells, T follicular helper cells, and regulatory T cells. As a consequence, B-cell activation and germinal center responses to high-fat diet are also markedly reduced. IRF8 deletion in DCs significantly reduces the development of atherosclerosis, predominantly in the aortic sinus, despite a modest increase in total plasma cholesterol levels. CONCLUSIONS: IRF8 expression in DCs plays a nonredundant role in the development of proatherogenic adaptive immunity.


Subject(s)
Adaptive Immunity , Atherosclerosis/immunology , Dendritic Cells/immunology , Interferon Regulatory Factors/metabolism , Animals , Aorta/cytology , Atherosclerosis/etiology , CD11 Antigens/genetics , CD11 Antigens/metabolism , Cells, Cultured , Diet, High-Fat/adverse effects , Female , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/metabolism , Interferon Regulatory Factors/genetics , Male , Mice , Mice, Inbred C57BL , T-Lymphocytes/immunology
16.
Circ Res ; 120(1): 78-84, 2017 Jan 06.
Article in English | MEDLINE | ID: mdl-27903567

ABSTRACT

RATIONALE: Deficiency of secreted IgM (sIgM-/-) accelerates atherosclerosis in Ldlr-/-mice. Several atheroprotective effects of increased levels of IgM antibodies have been suggested, including preventing inflammation induced by oxidized low-density lipoprotein and promoting apoptotic cell clearance. However, the mechanisms by which the lack of sIgM promotes lesion formation remain unknown. OBJECTIVE: To identify the mechanisms by which sIgM deficiency accelerates atherosclerosis in mice. METHODS AND RESULTS: We here show that both sIgM-/- and Ldlr-/-sIgM-/- mice develop increased plasma IgE titers because of impaired generation of B cells expressing the low-affinity IgE receptor CD23, which mediates the clearance of IgE antibodies. We further report that Ldlr-/-sIgM-/- mice exhibit increased numbers of activated mast cells and neutrophils in the perivascular area of atherosclerotic plaques. Treatment with an anti-IgE-neutralizing antibody fully reversed vascular inflammation and accelerated atherosclerotic lesion formation in cholesterol-fed Ldlr-/-sIgM-/- mice. CONCLUSIONS: Thus, our data identify a previously unsuspected mechanism by which sIgM deficiency aggravates atherosclerosis.


Subject(s)
Atherosclerosis/blood , Atherosclerosis/pathology , Immunoglobulin E/blood , Immunoglobulin M/deficiency , Animals , Biomarkers/blood , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout
17.
Cell Rep ; 14(10): 2348-61, 2016 Mar 15.
Article in English | MEDLINE | ID: mdl-26947073

ABSTRACT

Atherosclerosis is initiated and sustained by hypercholesterolemia, which results in the generation of oxidized LDL (OxLDL) and other metabolic byproducts that trigger inflammation. Specific immune responses have been shown to modulate the inflammatory response during atherogenesis. The sialic acid-binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of the functions of several immune cells, including myeloid cells and B-1 cells. Here, we show that deficiency of Siglec-G in atherosclerosis-prone mice inhibits plaque formation and diet-induced hepatic inflammation. We further demonstrate that selective deficiency of Siglec-G in B cells alone is sufficient to mediate these effects. Levels of B-1 cell-derived natural IgM with specificity for OxLDL were significantly increased in the plasma and peritoneal cavity of Siglec-G-deficient mice. Consistent with the neutralizing functions of OxLDL-specific IgM, Siglec-G-deficient mice were protected from OxLDL-induced sterile inflammation. Thus, Siglec-G promotes atherosclerosis and hepatic inflammation by suppressing protective anti-inflammatory effector functions of B cells.


Subject(s)
Atherosclerosis/pathology , Lectins/metabolism , Liver/metabolism , Receptors, Antigen, B-Cell/metabolism , Animals , Atherosclerosis/metabolism , B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Chemokines/analysis , Chemokines/blood , Cytokines/analysis , Cytokines/blood , Diet, High-Fat , Immunoassay , Immunoglobulin M/blood , Inflammation/pathology , Lectins/deficiency , Lectins/genetics , Leukocyte Common Antigens/metabolism , Lipoproteins, LDL/blood , Lipoproteins, LDL/immunology , Lipoproteins, LDL/metabolism , Liver/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Peritonitis/prevention & control , Peritonitis/veterinary , RNA, Messenger/metabolism , Receptors, Antigen, B-Cell/deficiency , Receptors, Antigen, B-Cell/genetics , Receptors, LDL/deficiency , Receptors, LDL/genetics , Serum Amyloid A Protein/analysis , Sialic Acid Binding Immunoglobulin-like Lectins
18.
J Clin Lipidol ; 9(4): 533-41, 2015.
Article in English | MEDLINE | ID: mdl-26228671

ABSTRACT

BACKGROUND: Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein currently established as an independent risk factor for the development of atherosclerotic disease and as a predictor for acute thrombotic complications. In addition, Lp(a) is the major carrier of proinflammatory oxidized phospholipids (OxPL). Today, atherosclerosis is considered to be an inflammatory disease of the vessel wall in which monocytes and monocyte-derived macrophages are crucially involved. Circulating monocytes can be divided according to their surface expression pattern of CD14 and CD16 into at least 3 subsets with distinct inflammatory and atherogenic potential. OBJECTIVE: The aim of this study was to examine whether elevated levels of Lp(a) and OxPL on apolipoprotein B-100-containing lipoproteins (OxPL/apoB) are associated with changes in monocyte subset distribution. METHODS: We included 90 patients with stable coronary artery disease. Lp(a) and OxPL/apoB were measured, and monocyte subsets were identified as classical monocytes (CMs; CD14++CD16-), intermediate monocytes (IMs; CD14++CD16+), and nonclassical monocytes (NCMs; CD14+CD16++) by flow cytometry. RESULTS: In patients with elevated levels of Lp(a) (>50 mg/dL), monocyte subset distribution was skewed toward an increase in the proportion of IM (7.0 ± 3.8% vs 5.2 ± 3.0%; P = .026), whereas CM (82.6 ± 6.5% vs 82.0 ± 6.8%; P = .73) and NCM (10.5 ± 5.3 vs 12.8 ± 6.0; P = .10) were not significantly different. This association was independent of clinical risk factors, choice of statin treatment regime, and inflammatory markers. In addition, OxPL/apoB was higher in patients with elevated Lp(a) and correlated with IM but not CM and NCM. CONCLUSIONS: In conclusion, we provide a potential link between elevated levels of Lp(a) and a proatherogenic distribution of monocyte subtypes in patients with stable atherosclerotic disease.


Subject(s)
Atherosclerosis/blood , Coronary Artery Disease/blood , Monocytes/metabolism , Oxidation-Reduction , Aged , Apolipoprotein B-100/blood , Atherosclerosis/pathology , Cell Lineage , Coronary Artery Disease/pathology , Female , GPI-Linked Proteins/blood , Humans , Lipopolysaccharide Receptors/blood , Lipoprotein(a)/blood , Male , Middle Aged , Monocytes/pathology , Phospholipids/blood , Receptors, IgG/blood , Risk Factors
19.
Oncol Rep ; 21(3): 787-91, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19212640

ABSTRACT

Avemar (MSC) is a nontoxic fermented wheat germ extract, which has been shown to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells. After 48 and 72 h of incubation, Avemar inhibited the growth of sensitive H9 cells with IC50 values of 290 and 200 microg/ml, whereas the growth of 5-FdUrd/Ara-C cross-resistant H9 cells was attenuated with IC50 values of 180 and 145 microg/ml, respectively. Treatment with 300 microg/ml MSC for 48 h caused dose-dependent induction of apoptosis in 48% of sensitive H9 cells. In cross-resistant H9 cells, incubation with 200 microg/ml Avemar for 48 h led to 41% of apoptotic tumor cells. Growth arrest of sensitive H9 cells after exposure to various concentrations of MSC occurred mainly in the S phase of the cell cycle, thereby increasing the cell population from 54 to 73% while depleting cells in the G0-G1 phase from 40 to 19%. Growth arrest in cross-resistant H9 cells occurred also mainly in the S phase, increasing the cell population from 45 to 68% while depleting cells in the G0-G1 phase from 45 to 31%. As MSC treatment likely overcomes 5-FdUrd/Ara-C resistance, further investigations to elucidate the exact mechanisms are warranted. We conclude that Avemar exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Lymphoma/drug therapy , Phytotherapy/methods , Plant Extracts/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cytarabine/pharmacology , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/physiology , Fluorouracil/pharmacology , Humans , Inhibitory Concentration 50
20.
Invest New Drugs ; 27(5): 393-401, 2009 Oct.
Article in English | MEDLINE | ID: mdl-18841326

ABSTRACT

Pancreatic cancer is a very aggressive malignant disease due to lack of early diagnosis and chemotherapeutic resistance of the tumor cells. There is distinct evidence that food derived polyphenols possess chemopreventive effects in the development of several cancers including pancreatic carcinoma. Resveratrol is one of those phenolic compounds found in grape skins and other fruits with known anticancer activity. Various polymethoxylated resveratrol derivatives showed stronger antiproliferative effects than resveratrol in tumor cell lines. The aim of our study was to evaluate the cytotoxic and biochemical effects of a newly synthesized polymethoxylated resveratrol analogue, N-hydroxy-N'-(3,4,5-trimethoxphenyl)-3,4,5-trimethoxy-benzamidine (KITC) in two human pancreatic cancer cell lines. The human pancreatic cancer cell lines, AsPC-1 and BxPC-3 were used to test the potential inhibitory effect of the resveratrol derivative on cell proliferation and the underlying mechanisms of this effect. After 7 days of incubation, KITC inhibited the growth of AsPC-1 and BxPC-3 cells with IC(50) values of 9.6 and 8.7 microM, respectively. KITC (40 microM) arrested cells in the G0/G1 phase and depleted cells in the S phase of the cell cycle (-105% and -35% of control, respectively). KITC induced dose-dependent apoptosis in both pancreatic cancer cell lines and was found to significantly reduce the in situ activity of ribonucleotide reductase, the key enzyme of DNA synthesis. Employing growth inhibition assays, KITC acted synergistically with gemcitabine in both cell lines. In summary, we found that KITC exerted considerable antitumor activity against human pancreatic cancer cells and could be a promising candidate for further investigations to establish a new chemotherapeutic regimen.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Pancreatic Neoplasms/drug therapy , Stilbenes/pharmacology , Antimetabolites, Antineoplastic/pharmacology , Antineoplastic Combined Chemotherapy Protocols , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Humans , Molecular Structure , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Ribonucleotide Reductases/antagonists & inhibitors , Ribonucleotide Reductases/metabolism , Tumor Cells, Cultured , Gemcitabine
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