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1.
Eur J Immunol ; : e2350851, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38803021

ABSTRACT

Stress exposure has been shown to modulate innate and adaptive immune responses. Indeed, stress favors myelopoiesis and monocyte generation and contributes to cardiovascular disease development. As sex hormones regulate innate and adaptive immune responses, we decided to investigate whether stress exposure leads to a different immune response in female and male mice. Our data demonstrated that psychosocial stressinduced neutrophilia in male, but not female mice. Importantly, we identified that B-cell numbers were reduced in female, but not male mice upon exposure to stress. Thus, our study revealed that the stress-induced immune alterations are sex-dependent, and this is an important feature to consider for future investigations.

2.
Cell Rep ; 39(11): 110949, 2022 06 14.
Article in English | MEDLINE | ID: mdl-35705045

ABSTRACT

Despite the ubiquitous function of macrophages across the body, the diversity, origin, and function of adrenal gland macrophages remain largely unknown. We define the heterogeneity of adrenal gland immune cells using single-cell RNA sequencing and use genetic models to explore the developmental mechanisms yielding macrophage diversity. We define populations of monocyte-derived and embryonically seeded adrenal gland macrophages and identify a female-specific subset with low major histocompatibility complex (MHC) class II expression. In adulthood, monocyte recruitment dominates adrenal gland macrophage maintenance in female mice. Adrenal gland macrophage sub-tissular distribution follows a sex-dimorphic pattern, with MHC class IIlow macrophages located at the cortico-medullary junction. Macrophage sex dimorphism depends on the presence of the cortical X-zone. Adrenal gland macrophage depletion results in altered tissue homeostasis, modulated lipid metabolism, and decreased local aldosterone production during stress exposure. Overall, these data reveal the heterogeneity of adrenal gland macrophages and point toward sex-restricted distribution and functions of these cells.


Subject(s)
Adrenal Glands , Macrophages , Monocytes , Sex Characteristics , Adrenal Glands/metabolism , Animals , Female , Histocompatibility Antigens Class II/genetics , Leukocyte Count , Macrophages/metabolism , Male , Mice
3.
Nat Metab ; 3(10): 1313-1326, 2021 10.
Article in English | MEDLINE | ID: mdl-34650273

ABSTRACT

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans.


Subject(s)
Amination , Glutamine/metabolism , Oxidative Phosphorylation , Animals , Mice , Phagocytosis
4.
Nat Commun ; 12(1): 5255, 2021 09 06.
Article in English | MEDLINE | ID: mdl-34489438

ABSTRACT

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling.


Subject(s)
Adipose Tissue, Brown/cytology , Monocytes/physiology , Adiponectin/genetics , Adipose Tissue, Brown/physiology , Animals , Cell Differentiation/genetics , Leukocyte Count , Macrophages/cytology , Macrophages/physiology , Membrane Glycoproteins/metabolism , Mice, Transgenic , Monocytes/cytology , Positron-Emission Tomography , Receptors, CCR2/genetics , Receptors, CCR2/metabolism
5.
Atherosclerosis ; 334: 1-8, 2021 10.
Article in English | MEDLINE | ID: mdl-34450556

ABSTRACT

Metabolism plays a key role in controlling immune cell functions. In this review, we will discuss the diversity of plaque resident myeloid cells and will focus on their metabolic demands that could reflect on their particular intraplaque localization. Defining the metabolic configuration of plaque resident myeloid cells according to their topologic distribution could provide answers to key questions regarding their functions and contribution to disease development.


Subject(s)
Atherosclerosis , Plaque, Atherosclerotic , Humans , Macrophages
6.
Infect Immun ; 89(9): e0073420, 2021 08 16.
Article in English | MEDLINE | ID: mdl-33820816

ABSTRACT

Along with respiratory tract disease per se, viral respiratory infections can also cause extrapulmonary complications with a potentially critical impact on health. In the present study, we used an experimental model of influenza A virus (IAV) infection to investigate the nature and outcome of the associated gut disorders. In IAV-infected mice, the signs of intestinal injury and inflammation, altered gene expression, and compromised intestinal barrier functions peaked on day 7 postinfection. As a likely result of bacterial component translocation, gene expression of inflammatory markers was upregulated in the liver. These changes occurred concomitantly with an alteration of the composition of the gut microbiota and with a decreased production of the fermentative, gut microbiota-derived products short-chain fatty acids (SCFAs). Gut inflammation and barrier dysfunction during influenza were not attributed to reduced food consumption, which caused in part gut dysbiosis. Treatment of IAV-infected mice with SCFAs was associated with an enhancement of intestinal barrier properties, as assessed by a reduction in the translocation of dextran and a decrease in inflammatory gene expression in the liver. Lastly, SCFA supplementation during influenza tended to reduce the translocation of the enteric pathogen Salmonella enterica serovar Typhimurium and to enhance the survival of doubly infected animals. Collectively, influenza virus infection can remotely impair the gut's barrier properties and trigger secondary enteric infections. The latter phenomenon can be partially countered by SCFA supplementation.


Subject(s)
Enterobacteriaceae Infections/etiology , Fatty Acids, Volatile/biosynthesis , Host-Pathogen Interactions , Influenza A virus/physiology , Influenza, Human/complications , Influenza, Human/virology , Intestinal Mucosa/metabolism , Microbial Interactions , Disease Susceptibility , Dysbiosis , Enterobacteriaceae Infections/metabolism , Host-Pathogen Interactions/immunology , Humans , Influenza, Human/metabolism , Intestinal Mucosa/immunology
7.
Nat Microbiol ; 6(3): 401-412, 2021 03.
Article in English | MEDLINE | ID: mdl-33432150

ABSTRACT

Inflammasomes are signalling platforms that are assembled in response to infection or sterile inflammation by cytosolic pattern recognition receptors. The consequent inflammasome-triggered caspase-1 activation is critical for the host defence against pathogens. During infection, NLRP3, which is a pattern recognition receptor that is also known as cryopyrin, triggers the assembly of the inflammasome-activating caspase-1 through the recruitment of ASC and Nek7. The activation of the NLRP3 inflammasome is tightly controlled both transcriptionally and post-translationally. Despite the importance of the NLRP3 inflammasome regulation in autoinflammatory and infectious diseases, little is known about the mechanism controlling the activation of NLRP3 and the upstream signalling that regulates the NLRP3 inflammasome assembly. We have previously shown that the Rho-GTPase-activating toxin from Escherichia coli cytotoxic necrotizing factor-1 (CNF1) activates caspase-1, but the upstream mechanism is unclear. Here, we provide evidence of the role of the NLRP3 inflammasome in sensing the activity of bacterial toxins and virulence factors that activate host Rho GTPases. We demonstrate that this activation relies on the monitoring of the toxin's activity on the Rho GTPase Rac2. We also show that the NLRP3 inflammasome is activated by a signalling cascade that involves the p21-activated kinases 1 and 2 (Pak1/2) and the Pak1-mediated phosphorylation of Thr 659 of NLRP3, which is necessary for the NLRP3-Nek7 interaction, inflammasome activation and IL-1ß cytokine maturation. Furthermore, inhibition of the Pak-NLRP3 axis decreases the bacterial clearance of CNF1-expressing UTI89 E. coli during bacteraemia in mice. Taken together, our results establish that Pak1 and Pak2 are critical regulators of the NLRP3 inflammasome and reveal the role of the Pak-NLRP3 signalling axis in vivo during bacteraemia in mice.


Subject(s)
Bacteremia/metabolism , Bacterial Toxins/metabolism , Escherichia coli Infections/metabolism , Escherichia coli Proteins/metabolism , Escherichia coli/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , rac GTP-Binding Proteins/metabolism , Animals , Bacteremia/immunology , Bacteremia/microbiology , Bacterial Load , Bacterial Toxins/genetics , Escherichia coli/genetics , Escherichia coli Infections/immunology , Escherichia coli Infections/microbiology , Escherichia coli Proteins/genetics , Immunity, Innate , Mice , Phosphorylation , Signal Transduction , p21-Activated Kinases/metabolism , rac GTP-Binding Proteins/genetics , RAC2 GTP-Binding Protein
8.
Cell Rep ; 30(10): 3397-3410.e5, 2020 03 10.
Article in English | MEDLINE | ID: mdl-32160545

ABSTRACT

Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rß signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis.


Subject(s)
ATP Binding Cassette Transporter 1/metabolism , Myeloproliferative Disorders/metabolism , ATP Binding Cassette Transporter 1/deficiency , ATP Binding Cassette Transporter 1/genetics , Animals , Cell Line, Tumor , Cell Transformation, Neoplastic/pathology , Cholesterol/metabolism , DNA-Binding Proteins/metabolism , Dioxygenases , Hematopoietic Stem Cells/metabolism , Humans , Interleukin-3/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Lipoproteins, HDL/metabolism , Loss of Function Mutation/genetics , Mice , Mice, Inbred C57BL , Myelopoiesis , Myeloproliferative Disorders/pathology , Proto-Oncogene Proteins/metabolism , Signal Transduction , Splenomegaly/pathology
9.
Eur J Immunol ; 49(11): 2012-2018, 2019 11.
Article in English | MEDLINE | ID: mdl-31251389

ABSTRACT

Macrophages play a central role during infection, inflammation and tissue homeostasis maintenance. Macrophages have been identified in all organs and their core transcriptomic signature and functions differ from one tissue to another. Interestingly, macrophages have also been identified in the peritoneal cavity and these cells have been extensively used as a model for phagocytosis, efferocytosis and polarization. Peritoneal macrophages are involved in B-cell IgA production, control of inflammation and wound healing following thermal-induced liver surface injury. These cells presumably require and interact with the omentum, where milky spot stromal cells have been proposed to secrete CSF1 (colony stimulating factor 1). Peritoneal macrophages depend on CSF1 for their generation and survival, but the identity of CSF1 producing cells inside the large peritoneal cavity remains unknown. Here we investigated peritoneal macrophage localization and their interaction with mesothelial cells, the major cell type predicted to secrete CSF1. Our data revealed that mesothelial cells produce membrane bound and secreted CSF1 that both sustain peritoneal macrophage growth.


Subject(s)
Epithelial Cells/metabolism , Epithelium/metabolism , Macrophage Colony-Stimulating Factor/genetics , Macrophages, Peritoneal/metabolism , Stromal Cells/metabolism , Animals , Cell Communication/genetics , Cell Communication/immunology , Cell Membrane/immunology , Cell Membrane/metabolism , Cell Survival , Coculture Techniques , Epithelial Cells/cytology , Epithelial Cells/immunology , Epithelium/immunology , Extracellular Space/immunology , Extracellular Space/metabolism , Gene Expression , Macrophage Colony-Stimulating Factor/immunology , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/immunology , Mice , Mice, Transgenic , Peritoneal Cavity/cytology , Signal Transduction , Stromal Cells/cytology , Stromal Cells/immunology
10.
Cardiovasc Res ; 115(9): 1393-1407, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31095280

ABSTRACT

Inflammation represents the driving feature of many diseases, including atherosclerosis, cancer, autoimmunity and infections. It is now established that metabolic processes shape a proper immune response and within this context the alteration in cellular cholesterol homeostasis has emerged as a culprit of many metabolic abnormalities observed in chronic inflammatory diseases. Cholesterol accumulation supports the inflammatory response of myeloid cells (i.e. augmentation of toll-like receptor signalling, inflammasome activation, and production of monocytes and neutrophils) which is beneficial in the response to infections, but worsens diseases associated with chronic metabolic inflammation including atherosclerosis. In addition to the innate immune system, cells of adaptive immunity, upon activation, have also been shown to undergo a reprogramming of cellular cholesterol metabolism, which results in the amplification of inflammatory responses. Aim of this review is to discuss (i) the molecular mechanisms linking cellular cholesterol metabolism to specific immune functions; (ii) how cellular cholesterol accumulation sustains chronic inflammatory diseases such as atherosclerosis; (iii) the immunometabolic profile of patients with defects of genes affecting cholesterol metabolism including familial hypercholesterolaemia, cholesteryl ester storage disease, Niemann-Pick type C, and immunoglobulin D syndrome/mevalonate kinase deficiency. Available data indicate that cholesterol immunometabolism plays a key role in directing immune cells function and set the stage for investigating the repurposing of existing 'metabolic' drugs to modulate the immune response.


Subject(s)
Cardiovascular Diseases/immunology , Cardiovascular System/immunology , Cholesterol/immunology , Energy Metabolism/immunology , Immune System/immunology , Immunomodulation , Inflammation Mediators/immunology , Inflammation/immunology , Animals , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/physiopathology , Cardiovascular System/metabolism , Cardiovascular System/physiopathology , Cholesterol/metabolism , Humans , Immune System/metabolism , Immune System/physiopathology , Inflammation/metabolism , Inflammation/physiopathology , Inflammation Mediators/metabolism , Signal Transduction
11.
Circ Res ; 122(10): 1369-1384, 2018 05 11.
Article in English | MEDLINE | ID: mdl-29523554

ABSTRACT

RATIONALE: Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. OBJECTIVE: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. METHODS AND RESULTS: We show that LIPA inhibition causes a defective efferocytic response because of impaired generation of 25-hydroxycholesterol and 27-hydroxycholesterol. Reduced synthesis of 25-hydroxycholesterol after LIPA inhibition contributed to defective mitochondria-associated membrane leading to mitochondrial oxidative stress-induced NLRP3 (NOD-like receptor family, pyrin domain containing) inflammasome activation and caspase-1-dependent Rac1 (Ras-related C3 botulinum toxin substrate 1) degradation. A secondary event consisting of failure to appropriately activate liver X receptor-mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. CONCLUSIONS: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.


Subject(s)
Cholesterol/metabolism , Inflammation/metabolism , Lysosomes/metabolism , Macrophages/metabolism , Oxysterols/metabolism , Sterol Esterase/metabolism , Animals , Apoptosis , Biological Transport , Cholesterol Esters/metabolism , Erythrocytes/metabolism , Hydrolysis , Hypercholesterolemia/metabolism , Inflammasomes/metabolism , Liver X Receptors/metabolism , Lymphocytes/metabolism , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neuropeptides/metabolism , Receptors, LDL/metabolism , Splenomegaly/metabolism , Sterol Esterase/antagonists & inhibitors , rac1 GTP-Binding Protein/metabolism
12.
Atherosclerosis ; 271: 102-110, 2018 04.
Article in English | MEDLINE | ID: mdl-29482037

ABSTRACT

The increasing incidence of obesity and its socio-economical impact is a global health issue due to its associated co-morbidities, namely diabetes and cardiovascular disease [1-5]. Obesity is characterized by an increase in adipose tissue, which promotes the recruitment of immune cells resulting in low-grade inflammation and dysfunctional metabolism. Macrophages are the most abundant immune cells in the adipose tissue of mice and humans. The adipose tissue also contains other myeloid cells (dendritic cells (DC) and neutrophils) and to a lesser extent lymphocyte populations, including T cells, B cells, Natural Killer (NK) and Natural Killer T (NKT) cells. While the majority of studies have linked adipose tissue macrophages (ATM) to the development of low-grade inflammation and co-morbidities associated with obesity, emerging evidence suggests for a role of other immune cells within the adipose tissue that may act in part by supporting macrophage homeostasis. In this review, we summarize the current knowledge of the functions ATMs, DCs and B cells possess during steady-state and obesity.


Subject(s)
Adipose Tissue/immunology , B-Lymphocytes/immunology , Dendritic Cells/immunology , Macrophages/immunology , Obesity/immunology , Adipokines/metabolism , Adipose Tissue/metabolism , Adipose Tissue/physiopathology , Adiposity , Animals , B-Lymphocytes/metabolism , Cell Communication , Cytokines/metabolism , Dendritic Cells/metabolism , Humans , Inflammation Mediators/metabolism , Macrophages/metabolism , Obesity/metabolism , Obesity/physiopathology , Phenotype , Signal Transduction
13.
Mediators Inflamm ; 2018: 2426138, 2018.
Article in English | MEDLINE | ID: mdl-30647530

ABSTRACT

Monocyte and macrophage diversity is evidenced by the modulation of cell surface markers and differential production of soluble mediators. These immune cells play key roles in controlling tissue homeostasis, infections, and excessive inflammation. Macrophages remove dead cells in a process named efferocytosis, contributing to the healthy tissue maintenance. Recently, it became clear that the main macrophage functions are under metabolic control. Modulation of glucose, fatty acid, and amino acid metabolism is associated with various macrophage activations in response to external stimuli. Deciphering these metabolic pathways provided critical information about macrophage functions.


Subject(s)
Macrophage Activation/physiology , Macrophages/metabolism , Amino Acids/metabolism , Animals , Fatty Acids/metabolism , Glucose/metabolism , Humans , Phagocytosis/physiology
14.
Circ Res ; 118(7): 1062-77, 2016 Apr 01.
Article in English | MEDLINE | ID: mdl-26926469

ABSTRACT

RATIONALE: Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with (18)F-fluorodeoxyglucose, a glucose analog, but the underlying mechanisms are poorly understood. OBJECTIVE: Here, we directly investigated the role of Glut1-mediated glucose uptake in apolipoprotein E-deficient (ApoE(-/-)) mouse model of atherosclerosis. METHODS AND RESULTS: We first showed that the enhanced glycolytic flux in atheromatous plaques of ApoE(-/-) mice was associated with the enhanced metabolic activity of hematopoietic stem and multipotential progenitor cells and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE(-/-) hematopoietic stem and multipotential progenitor cells was not because of alterations in hypoxia-inducible factor 1α signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common ß subunit of the granulocyte-macrophage colony-stimulating factor/interleukin-3 receptor driving glycolytic substrate utilization by mitochondria. By transplanting bone marrow from WT, Glut1(+/-), ApoE(-/-), and ApoE(-/-)Glut1(+/-) mice into hypercholesterolemic ApoE-deficient mice, we found that Glut1 deficiency reversed ApoE(-/-) hematopoietic stem and multipotential progenitor cell proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE(-/-) mice transplanted with ApoE(-/-) bone marrow and resulted in reduced glucose uptake in the spleen and aortic arch of these mice. CONCLUSIONS: We identified that Glut1 connects the enhanced glucose uptake in atheromatous plaques of ApoE(-/-) mice with their myelopoiesis through regulation of hematopoietic stem and multipotential progenitor cell maintenance and myelomonocytic fate and suggests Glut1 as potential drug target for atherosclerosis.


Subject(s)
Glucose Transporter Type 1/physiology , Glucose/metabolism , Hematopoietic Stem Cells/metabolism , Hypercholesterolemia/metabolism , Myelopoiesis/physiology , Plaque, Atherosclerotic/metabolism , Animals , Aorta, Thoracic/metabolism , Apolipoproteins E/deficiency , Bone Marrow Transplantation , Cell Division , Cytokine Receptor Common beta Subunit/physiology , Disease Progression , Energy Metabolism , Gene Expression Regulation , Glucose Transporter Type 1/deficiency , Glycolysis , Hypercholesterolemia/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/deficiency , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Metformin/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Multipotent Stem Cells/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Interleukin-3/antagonists & inhibitors , Receptors, Interleukin-3/physiology , Spleen/metabolism , Tyrphostins/pharmacology
15.
Cell Rep ; 13(1): 132-144, 2015 Oct 06.
Article in English | MEDLINE | ID: mdl-26411684

ABSTRACT

Enhanced glucose utilization can be visualized in atherosclerotic lesions and may reflect a high glycolytic rate in lesional macrophages, but its causative role in plaque progression remains unclear. We observe that the activity of the carbohydrate-responsive element binding protein ChREBP is rapidly downregulated upon TLR4 activation in macrophages. ChREBP inactivation refocuses cellular metabolism to a high redox state favoring enhanced inflammatory responses after TLR4 activation and increased cell death after TLR4 activation or oxidized LDL loading. Targeted deletion of ChREBP in bone marrow cells resulted in accelerated atherosclerosis progression in Ldlr(-/-) mice with increased monocytosis, lesional macrophage accumulation, and plaque necrosis. Thus, ChREBP-dependent macrophage metabolic reprogramming hinders plaque progression and establishes a causative role for leukocyte glucose metabolism in atherosclerosis.


Subject(s)
Atherosclerosis/immunology , Macrophages/immunology , Nuclear Proteins/immunology , Plaque, Atherosclerotic/immunology , Receptors, LDL/immunology , Transcription Factors/immunology , Animals , Apoptosis/drug effects , Atherosclerosis/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Bone Marrow Cells/drug effects , Bone Marrow Cells/immunology , Bone Marrow Cells/pathology , Female , Gene Expression Regulation , Glucose/metabolism , Glycolysis/genetics , Humans , Inflammation , Lipoproteins, LDL/pharmacology , Macrophage Activation/drug effects , Macrophages/drug effects , Macrophages/pathology , Mice , Mice, Knockout , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Oxidation-Reduction , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/pathology , Primary Cell Culture , Receptors, LDL/deficiency , Receptors, LDL/genetics , Signal Transduction , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunology , Toll-Like Receptor 4/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
16.
PLoS One ; 7(11): e49419, 2012.
Article in English | MEDLINE | ID: mdl-23173060

ABSTRACT

We compared gene expression signatures of aggressive amelanotic (Amela) melanomas with those of slowly growing pigmented melanomas (Mela), identifying pathways potentially responsible for the aggressive Amela phenotype. Both tumors develop in mice upon conditional deletion in melanocytes of Ink4a/Arf tumor suppressor genes with concomitant expression of oncogene H-Ras(G12V) and a known tumor antigen. We previously showed that only the aggressive Amela tumors were highly infiltrated by leukocytes concomitant with local and systemic inflammation. We report that Amela tumors present a pattern of de-differentiation with reduced expression of genes involved in pigmentation. This correlates with reduced and enhanced expression, respectively, of microphthalmia-associated (Mitf) and Pou3f2/Brn-2 transcription factors. The reduced expression of Mitf-controlled melanocyte differentiation antigens also observed in some human cutaneous melanoma has important implications for immunotherapy protocols that generally target such antigens. Induced Amela tumors also express Epithelial-Mesenchymal-Transition (EMT)-like and TGFß-pathway signatures. These are correlated with constitutive Smad3 signaling in Amela tumors and melanoma cell lines. Signatures of infiltrating leukocytes and some chemokines such as chemotactic cytokine ligand 2 (Ccl2) that contribute to leukocyte recruitment further characterize Amela tumors. Inhibition of the mitogen-activated protein kinase (MAPK) activation pathway in Amela tumor lines leads to reduced expression of EMT hallmark genes and inhibits both proinflammatory cytokine Ccl2 gene expression and Ccl2 production by the melanoma cells. These results indicate a link between EMT-like processes and alterations of immune functions, both being controlled by the MAPK pathway. They further suggest that targeting the MAPK pathway within tumor cells will impact tumor-intrinsic oncogenic properties as well as the nature of the tumor microenvironment.


Subject(s)
Epithelial-Mesenchymal Transition , Melanoma, Amelanotic/pathology , Signal Transduction , Skin Neoplasms/pathology , Transforming Growth Factor beta/metabolism , Animals , Cell Differentiation , Cell Line, Tumor , Chemokine CCL2/metabolism , Down-Regulation , Enzyme Activation , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , MAP Kinase Signaling System , Melanocytes/metabolism , Melanocytes/pathology , Melanoma, Amelanotic/genetics , Melanoma, Amelanotic/metabolism , Melanoma, Experimental/genetics , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Mice , Mitogen-Activated Protein Kinases/metabolism , Nerve Tissue Proteins/genetics , POU Domain Factors/genetics , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Smad3 Protein/metabolism , Up-Regulation
17.
J Immunol ; 180(12): 8153-8, 2008 Jun 15.
Article in English | MEDLINE | ID: mdl-18523280

ABSTRACT

TGF-beta family cytokines play multiple roles in immune responses. TGF-beta1-null mice suffer from multi-organ infiltration that leads to their premature death. T cells play a central role in the TGF-beta1 phenotype, as deficiency of TGF-beta1 only in T cells reproduces the lethal phenotype. Although it is known that TGF-beta1 controls B cells isotype switch and homeostasis, the source responsible for this control has not been characterized. Because of the major role that T cells play in regulating B cell responses, we addressed the T cell dependency of the TGF-beta1 control of B cells. The analysis of T cell-deficient, TGF-beta1 knockout mice and the production of chimeras in which B but not T cells lacked TGF-beta1 allowed us to show that B cells are controlled in part by cell autonomous production of TGF-beta1.


Subject(s)
B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Transforming Growth Factor beta1/physiology , Animals , Antigens, T-Independent/genetics , Antigens, T-Independent/physiology , CD3 Complex/genetics , Crosses, Genetic , Homeostasis/genetics , Homeostasis/immunology , Immunoglobulin Class Switching/genetics , Immunoglobulin Isotypes/biosynthesis , Immunoglobulin Isotypes/genetics , Mice , Mice, Knockout , Radiation Chimera/genetics , Radiation Chimera/immunology , Spleen/cytology , Spleen/immunology , Spleen/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Transforming Growth Factor beta1/biosynthesis , Transforming Growth Factor beta1/genetics
18.
Eur J Immunol ; 38(5): 1257-63, 2008 May.
Article in English | MEDLINE | ID: mdl-18412162

ABSTRACT

Thymic dendritic cells (DC) and epithelial cells play a major role in central tolerance but their respective roles are still controversial. Epithelial cells have the unique ability to ectopically express peripheral tissue-restricted antigens conferring self-tolerance to tissues. Paradoxically, while negative selection seems to occur for some of these antigens, epithelial cells, contrary to DC, are poor negative selectors. Using a thymic epithelial cell line, we show the functional intercellular transfer of membrane material, including MHC molecules, occurring between epithelial cells. Using somatic and bone marrow chimeras, we show that this transfer occurs efficiently in vivo between epithelial cells and, in a polarized fashion, from epithelial to DC. This novel mode of transfer of MHC-associated, epithelial cell-derived self-antigens onto DC might participate to the process of negative selection in the thymic medulla.


Subject(s)
Biological Transport/immunology , Cell Communication/immunology , Dendritic Cells/metabolism , Epithelial Cells/metabolism , Histocompatibility Antigens/metabolism , Thymus Gland/cytology , Amidohydrolases/metabolism , Animals , Antigens/immunology , Antigens/metabolism , Antigens, Neoplasm/analysis , Bone Marrow Transplantation , Cell Adhesion Molecules/analysis , Cell Adhesion Molecules/metabolism , Cell Line , Chimera/genetics , Chimera/immunology , Dendritic Cells/cytology , Dendritic Cells/immunology , Epithelial Cell Adhesion Molecule , Epithelial Cells/cytology , Epithelial Cells/immunology , Fluorescent Dyes/metabolism , GPI-Linked Proteins , H-2 Antigens/genetics , H-2 Antigens/metabolism , Histocompatibility Antigens/genetics , Histocompatibility Antigens Class II/metabolism , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Knockout , Pseudopodia/immunology , Pseudopodia/metabolism , T-Lymphocytes/immunology , Thymus Gland/immunology
19.
Gene ; 359: 18-25, 2005 Oct 10.
Article in English | MEDLINE | ID: mdl-16107303

ABSTRACT

A rare mRNA variant of the human lymphocyte-specific protein tyrosine kinase LCK gene that retains intron B and excludes exon 7 (B+7-) due to alternative splicing of the canonical LCK transcripts was identified and characterized. LCK B+7- mRNA is detected in all tested peripheral blood T lymphocytes total RNA samples but is apparently sequestered in the nucleus. The presence of intron B sequence does not disrupt the reading frame and results in the insertion of 58 aminoacids, containing a proline-rich region just upstream of p56lck SH3 domain. This putative isoform encodes an unstable 516 aminoacids protein (LckB+7-) which can be expressed in transfected COS-7 cells. Furthermore in Jurkat T cell extracts, a recombinant intron B plus SH3 p56lck domain fails to interact with some TCR-induced tyrosine phosphorylated polypeptides and known p56lck partners such as Sam68 and c-Cbl. The biological function of this rare messenger remains to be elucidated.


Subject(s)
Alternative Splicing , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics , RNA, Messenger/genetics , src Homology Domains/genetics , Amino Acid Sequence , Animals , Base Sequence , Blotting, Western , COS Cells , Cells, Cultured , Chlorocebus aethiops , Cloning, Molecular , DNA, Complementary/chemistry , DNA, Complementary/genetics , Humans , Introns/genetics , Isoenzymes/genetics , Isoenzymes/metabolism , Jurkat Cells , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Molecular Sequence Data , Mutagenesis, Insertional , Protein Binding , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sequence Alignment , Sequence Analysis, DNA , Sequence Homology, Nucleic Acid , T-Lymphocytes/cytology , T-Lymphocytes/enzymology , T-Lymphocytes/metabolism , Transcription, Genetic/genetics
20.
Mol Cell Biol ; 25(11): 4455-65, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15899851

ABSTRACT

NTAL (non-T-cell activation linker, also called LAB) and LAT (linker for activation of T cells) are evolutionarily related transmembrane adaptor proteins that are phosphorylated upon immunoreceptor engagement. Using quantitative reverse transcription-PCR, both NTAL and LAT were found to be expressed in B cells. However, LAT expression was limited to early B cells, whereas NTAL expression typified mature B cells. To delineate their roles in B-cell development and function, Ntal-deficient mice were generated and crossed with Lat-deficient mice. B cells developed in Lat(-/-) Ntal(-/-) double-deficient mice and in mice lacking either of the two adaptors with the same efficiency as in wild-type mice. Upon B-cell antigen receptor cross-linking, Ntal(-/-) B cells exhibited slightly increased Ca(2+) mobilization and proliferation. In addition, Ntal-deficient mice had increased levels of natural antibodies and slightly increased humoral response to a T-dependent antigen. Normal titers of serum-specific immunoglobulins were produced in response to a T-cell-independent antigen. Although NTAL is also expressed in plasma cells, its absence did not affect the hypergammaglobulinemia E and G1 that developed in mice with a mutation in tyrosine 136 of LAT. Therefore, NTAL does not play a role in B cells symmetric to the role played by LAT in T cells.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Adaptor Proteins, Vesicular Transport/physiology , B-Lymphocytes/immunology , Membrane Proteins/physiology , Phosphoproteins/physiology , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Vesicular Transport/deficiency , Adaptor Proteins, Vesicular Transport/genetics , Animals , Antibody Formation , Antigens, T-Independent/immunology , B-Lymphocytes/drug effects , Calcium/pharmacology , Cell Differentiation , Cell Proliferation , Gene Deletion , Gene Expression , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice , Mice, Mutant Strains , Mutation , Phosphoproteins/deficiency , Phosphoproteins/genetics , Plasma Cells/immunology , RNA, Messenger/analysis , RNA, Messenger/metabolism , T-Lymphocytes/immunology , Tyrosine/genetics
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