
Carlos ArdavínSpanish National Research Council | CSIC · Spanish National Center for Biotechnology
Carlos Ardavín
PhD
Research Professor at the National Center for Biotechnology, Madrid, Spain
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Introduction
Research performed in Carlos Ardavin's lab aims at exploring the role of inflammatory monocytes and macrophages during infection, allergy and intraperitoneal tumour metastasis.
Publications
Publications (96)
Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute t...
Resident peritoneal macrophages (resMØs) are crucial for repairing peritoneal injuries and controlling infections by forming mesothelium-bound resMØ-aggregates in the peritoneal wall and omentum. Here we present a protocol to analyze these structures in mouse models of peritoneal inflammation. We describe the dissection, fixation, immunofluorescent...
Large peritoneal macrophages (LPMs) are long‐lived, tissue‐resident macrophages, formed during embryonic life, developmentally and functionally confined to the peritoneal cavity. LPMs provide the first line of defense against life‐threatening pathologies of the peritoneal cavity, such as abdominal sepsis, peritoneal metastatic tumor growth, or peri...
MV130 is an inactivated polybacterial mucosal vaccine that confers protection to patients against recurrent respiratory infections, including those of viral etiology. However, its mechanism of action remains poorly understood. Here, we find that intranasal prophylaxis with MV130 modulates the lung immune landscape and provides long-term heterologou...
Peritoneal immune cells reside unanchored within the peritoneal fluid in homeostasis. Here, we examined the mechanisms that control bacterial infection in the peritoneum using a mouse model of abdominal sepsis following intraperitoneal Escherichia coli infection. Whole-mount immunofluorescence and confocal microscopy of the peritoneal wall and omen...
IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-i...
Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans We describe a new TAK1...
The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such...
GM-CSF promotes the functional maturation of lung alveolar macrophages (A-MØ), whose differentiation is dependent on the peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor. In fact, blockade of GM-CSF-initiated signaling or deletion of the PPARγ-encoding gene PPARG leads to functionally defective A-MØ and the onset of pul...
Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyph...
Neutrophils play a crucial role in defense against systemic candidiasis, a disease associated with a high mortality rate in patients receiving immunosuppressive therapy, although the early immune mechanisms that boost the candidacidal activity of neutrophils remain to be defined in depth. Here, we used a murine model of systemic candidiasis to expl...
Abstract Modern subunit vaccines require the development of new adjuvant strategies. Recently, we showed that CpG-ODN formulated with a liquid crystal nanostructure formed by self-assembly of 6-O-ascorbyl palmitate (Coa-ASC16) is an attractive system for promoting an antigen-specific immune response to weak antigens. Here, we showed that after subc...
Despite recent evidence on the involvement of CD81 in pathogen binding and Ag presentation by dendritic cells (DCs), the molecular mechanism of how CD81 regulates immunity during infection remains to be elucidated. To investigate the role of CD81 in the regulation of defense mechanisms against microbial infections, we have used the Listeria monocyt...
The CCL2 chemokine mediates monocyte egress from bone marrow and recruitment into inflamed tissues through interaction with the CCR2 chemokine receptor, and its expression is upregulated by proinflammatory cytokines. Analysis of the gene expression profile in GM-CSF- and M-CSF-polarized macrophages revealed that a high CCL2 expression characterizes...
Background Whereas recent research has characterized the mechanism by which dendritic cells (DCs) induce TH1/TH17 responses, the functional specialization enabling DCs to polarize TH2 responses remains undefined. Because IL-4 is essential during TH2 responses not only by acting on CD4⁺ T cells through the activation of GATA-3 but also by regulating...
Whereas recent research has characterized the mechanism by which dendritic cells (DCs) induce TH1/TH17 responses, the functional specialization enabling DCs to polarize TH2 responses remains undefined. Because IL-4 is essential during TH2 responses not only by acting on CD4(+) T cells through the activation of GATA-3 but also by regulating IgE clas...
Type I interferon (IFN) is crucial during infection through its antiviral properties and by coordinating the immunocompetent cells involved in antiviral or antibacterial immunity. Type I IFN (IFN-α and IFN-β) is produced after virus or bacteria recognition by cytosolic receptors or membrane-bound TLR receptors following the activation of the transc...
Cervical cancer is caused by persistent high-risk human papillomavirus (HR-HPV) infection and represents the second most frequent gynecological malignancy in the world. The HPV-16 type accounts for up to 55% of all cervical cancers. The HPV-16 oncoproteins E6 and E7 are necessary for induction and maintenance of malignant transformation and represe...
In vitro maturation of DCs. A) Scheme of the differentiation and maturation process. For differentiation into immature DCs, murine monocytes were incubated only with GM-CSF, whereas human monocytes were incubated with both GM-CSF and IL-4. The surface markers used in this study are shown in the figure (h; human, m; murine). B) Human DC activation....
IL-12 p70 and IL-6 production. Production of cytokines was analyzed by ELISA after stimulation of immature DCs with either 5 µg/ml LPS, IBDV-VLP (2 µg/ml and 0.5 µg/ml) or PBS alone (control). Bars represent mean ± s.e.m. of triplicates.
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Monocytes have the capacity to differentiate into macrophages or dendritic cells (DCs) after extravasation into lymphoid and nonlymphoid tissues. They have thus been consequently considered as precursors, but not effector cells, recirculating exclusively through the blood. In this report, we demonstrate for the first time that, after subcutaneous i...
On the basis mainly of pharmacological experiments, the p38α MAP kinase isoform has been established as an important regulator of immune and inflammatory responses. However, the role of the related p38γ and p38δ kinases has remained unclear. Here, we show that deletion of p38γ and p38δ impaired the innate immune response to lipopolysaccharide (LPS)...
Statins are prescribed to 25 million people worldwide for treating hypercholesterolemia and reducing the risk of cardiovascular diseases. However, the side effects of statins on immunity, and particularly on DC immunobiology, have not been analyzed in-depth. Here, we have investigated the impact of lovastatin treatment during monocyte differentiati...
We have analyzed morphological changes affecting the lympho-hemopoietic organs of the anadromous sea lamprey, Petromyzon marinus throughout its life span. For this analysis, ammocoetes (2–4 years), premetamorphosing lampreys (nearly 5 years), metamorphosing lampreys, macrophtalmia stages (young adults) and parasitic adults (nearly 7 years) were use...
Although monocytes were originally described as precursors to all the different subpopulations of macrophages found in the steady state and formed under inflammatory and infectious conditions, recent data have demonstrated conclusively that monocytes can also differentiate into dendritic cells (DCs). Monocytes are the precursors to different subset...
The statins, a group of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are reported to influence a variety of immune system activities through 3-hydroxy-3-methylglutaryl coenzyme A reductase-dependent and -independent mechanisms. How statin treatment regulates immune system function in vivo nonetheless remains to be fully define...
Specific defense mechanisms against pathogens are fulfilled by different subsets of nonmucosal conventional dendritic cells (DCs), including migratory Langerhans cells (LCs), dermal DCs, and resident CD8(+) and CD8(-) DCs found in lymphoid organs. Dermal DCs capture antigens in the skin and migrate to lymph nodes, where they can transfer the antige...
Plasmacytoid dendritic cells (pDCs) efficiently produce type I interferon and participate in adaptive immune responses, although the molecular interactions between pDCs and antigen-specific T cells remain unknown. This study examines immune synapse (IS) formation between murine pDCs and CD4(+) T cells. Mature pDCs formed canonical ISs, involving re...
Improvement of the strategy to target tumor Ags to dendritic cells (DCs) for immunotherapy requires the identification of the most appropriate ligand/receptor pairing. We screened a library of Ab fragments on mouse DCs to isolate new potential Abs capable of inducing protective immune responses. The screening identified a high-affinity Ab against C...
Monocyte recruitment and differentiation into dendritic cells or macrophages play a critical role in defense mechanisms against pathogens and in inflammatory and autoimmune diseases. Important contributions have been made on the molecular events controlling neutrophil and lymphocyte extravasation under steady state or inflammation. However, the mol...
Monocytes have been classically considered essential elements in relation with innate immune responses against pathogens, and inflammatory processes caused by external aggressions, infection and autoimmune disease. However, although their potential to differentiate into dendritic cells (DCs) was discovered 14 years ago, their functional relevance w...
Infection-induced inflammatory reactions involve a strong increase in dendritic cells (DCs) at the infection site and draining lymph nodes (dLNs). Whether inflammatory DCs are recruited to these locations or differentiate locally, and what their functional relevance is, remain unclear. Here we showed that during Leishmania infection, monocytes were...
Emerging evidence suggests that dendritic cells play a major role in the orchestration of the immune response to bacteria. This volume introduces the reader to the complex world of dendritic cells and describes how the intimate interplay between dendritic cells, bacteria and the environment dictates either the induction of immunity or tolerance to...
Expression of the physiological cellular prion protein (PrP(C)) is remarkably regulated during differentiation and activation of cells of the immune system. Among these, dendritic cells (DCs) display particularly high levels of membrane PrP(C), which increase upon maturation, in parallel with that of molecules involved in Ag presentation to T cells...
CD36 is a member of the scavenger receptor type B family implicated in the binding of lipoproteins, phosphatidylserine, thrombospondin-1, and the uptake of long-chain fatty acids. On mononuclear phagocytes, recognition of apoptotic cells by CD36 contributes to peripheral tolerance and prevention of autoimmunity by impairing dendritic cell (DC) matu...
It has been recently demonstrated that, in addition to function as macrophage precursors, monocytes have the capacity to differentiate into dendritic cells (DCs), and therefore they play an essential role in both the innate and adaptive immunity. Monocytes display a remarkable functional diversity, allowing them to perform multiple defense function...
Although dendritic cells (DCs) regulate immune responses, they exhibit functional heterogeneity depending on their anatomical location. We examined the functional properties of intestinal DCs after oral administration of cholera toxin (CT), the most potent mucosal adjuvant. Two CD11c+ DC subsets were identified both in Peyer's patches and mesenteri...
Nature 415, 1043–1047 (2002). In this Letter, we characterized a common precursor population for dendritic cells (DCs) isolated from mouse blood by their capacity to generate all DC subpopulations present in mouse lymphoid organs after transfer into irradiated recipients, including CD8- and CD8+ DCs, as well as B220+ plasmacytoid DCs.
The monocyte capacity to differentiate into dendritic cells (DCs) was originally demonstrated by human in vitro DC differentiation assays that have subsequently become the essential methodologic approach for the production of DCs to be used in DC-mediated cancer immunotherapy protocols. In addition, in vitro DC generation from monocytes is a powerf...
A recent workshop on "Dendritic Cells: Biology and Therapeutic Applications," sponsored by the Juan March Foundation, brought together basic and clinical research scientists to discuss the mechanisms underlying the control of immune responses and tolerance by dendritic cells (DCs), as well as recent research in cancer immunotherapy based on DC vacc...
A recent workshop on “Dendritic Cells: Biology and Therapeutic Applications,” sponsored by the Juan March Foundation, brought together basic and clinical research scientists to discuss the mechanisms underlying the control of immune responses and tolerance by dendritic cells (DCs), as well as recent research in cancer immunotherapy based on DC vacc...
Dendritic cells (DCs) are key elements of the immune system due to their essential role in the induction and control of T cell responses. The enormous potential of DCs as antigen-presenting cells relies on their capacity to capture, process and present a wide diversity of antigens to T cells with a very high efficiency, as well as on their capacity...
Functional specialization allows defined dendritic-cell (DC) subsets to induce efficient defence mechanisms against pathogens and tumour cells, and maintain T-cell tolerance by inducing the inactivation of autoreactive T cells. A crucial question, which has important implications for both our understanding of the induction and control of immunity b...
We describe a new B220+ subpopulation of immaturelike dendritic cells (B220+ DCs) with low levels of expression of major histocompatibility complex (MHC) and costimulatory molecules and markedly reduced T-cell stimulatory potential, located in the thymus, bone marrow, spleen, and lymph nodes. B220+ DCs display ultrastructural characteristics resemb...
Dendritic cells (DCs) are essential for the establishment of immune responses against pathogens and tumour cells, and thus have great potential as tools for vaccination and cancer immunotherapy trials. Experimental evidence has led to a dual DC differentiation model, which involves the existence of both myeloid- and lymphoid-derived DCs. But this c...
Despite the information dealing with the differential phenotype and function of the main mouse dendritic cell (DC) subpopulations, namely, CD8alpha(-) and CD8alpha(+) DCs, their origin and involvement in antiviral immune responses in vivo are still largely unknown. To address these issues, this study used the changes occurring in DC subpopulations...
CD8alpha+ and CD8alpha- dendritic cells (DCs) have been considered as independent DC subpopulations both ontogenetically and functionally during recent years. However, it has been demonstrated that both DC subsets can be generated from a single precursor population, supporting the concept that they do not represent separate DC lineages. By using hi...
Despite extensive, recent research on the development of dendritic cells (DCs), their origin is a controversial issue in immunology, with important implications regarding their use in cancer immunotherapy. Although, under defined experimental conditions, DCs can be generated from myeloid or lymphoid precursors, the differentiation pathways that gen...
Two dendritic cell (DC) subsets have been identified in the murine system on the basis of their differential CD8 alpha expression. CD8 alpha(+) DCs and CD8 alpha(-) DCs are considered as lymphoid- and myeloid-derived, respectively, because CD8 alpha(+) but not CD8 alpha(-) splenic DCs were generated from lymphoid CD4(low) precursors, devoid of myel...
Chemokines appear to have an important role in the seeding of lymphoid progenitors in the thymus, the regulation of the coordinated movements of the maturing T cells within this organ, and the egress of the resulting naive T cells to secondary lymphoid organs. CCR9, the specific receptor for the beta-chemokine TECK/CCL25, is selectively expressed i...
The method described in this chapter for the isolation of mouse thymic dendritic cells (DC) is an optimization of our previously published methods (1,2) and involves the following major steps: 1. Enzymatic digestion of thymic fragments with collagenase and DNase. 2. Separation of a very-low-density cell fraction (VLDF). 3. Magnetic depletion of T-l...
Two dendritic cell (DC) subsets have been identified in the murine system on the basis of their differential CD8alpha expression. CD8alpha(+) DCs and CD8alpha(-) DCs are considered as lymphoid- and myeloid-derived, respectively, because CD8alpha(+) but not CD8alpha(-) splenic DCs were generated from lymphoid CD4(low) precursors, devoid of myeloid r...
Langerhans cells (LCs) are specialized dendritic cells (DCs) strategically located in stratified epithelia, such as those of the skin, oral cavity, pharynx, esophagus, upper airways, urethra, and female reproductive tract, which are exposed to a wide variety of microbial pathogens. LCs play an essential role in the induction of T-lymphocyte respons...
Two dendritic cell (DC) subsets have been identified in the murine system on the basis of their differential CD8α expression. CD8α+ DCs and CD8α− DCs are considered as lymphoid- and myeloid-derived, respectively, because CD8α+ but not CD8α− splenic DCs were generated from lymphoid CD4low precursors, devoid of myeloid reconstitution potential. Altho...
Langerhans cells (LCs) are specialized dendritic cells (DCs) strategically located in stratified epithelia, such as those of the skin, oral cavity, pharynx, esophagus, upper airways, urethra, and female reproductive tract, which are exposed to a wide variety of microbial pathogens. LCs play an essential role in the induction of T-lymphocyte respons...
Dendritic cell (DC) reconstitution experiments and phenotypic analysis of DC subpopulations have allowed the definition in the mouse of two main DC categories: CD8+ lymphoid DCs and CD8- myeloid DCs. With regard to Langerhans cells (LCs), which represent immature DCs differentiating into mature DCs on migration to the lymph nodes after an antigenic...
Thymus-expressed chemokine (TECK) has been reported to chemoattract dendritic cells, thymocytes, and activated macrophages. Here, we show that TECK is a specific agonist for a human orphan receptor called GPR-9-6. We have determined the cDNA sequence of human GPR-9-6 and cloned the corresponding murine cDNA. Human and murine GPR-9-6 expression is v...
The phenotype of mouse thymic B cells and their capacity to induce T cell negative selection in vitro were analyzed. Thymic B cells expressed B cell markers such as IgM, Fc receptor, CD44, heat-stable antigen, LFA-1 and CD40. In addition, they were positive for the activation molecule CD69 and displayed high levels of B7-2. Although thymic B cells...
The immune response to mouse mammary tumor virus (MMTV) relies on the presentation of an MMTV-encoded superantigen by infected B cells to superantigen-specific T cells. The initial extrafollicular B cell differentiation involved the generation of B cells expressing low levels of B220. These B220low B cells corresponded to plasmablasts that expresse...
Dendritic cells (DC) are highly efficient antigen-presenting cells (APC) that have an essential function in the development of immune responses against microbial pathogens and tumors. Although during the past few years our understanding of DC biology has remarkably increased, a precise characterization of the different DC subpopulations remains to...
Dendritic cells (DC) are highly efficient antigen-presenting cells (APC) that have an essential function in the development of immune responses against microbial pathogens and tumors. Although during the past few years our understanding of DC biology has remarkably increased, a precise characterization of the different DC subpopulations remains to...
We have cloned the murine CCR6 receptor and its ligand, the beta-chemokine mMIP-3alpha. Calcium mobilization assays performed with mCCR6 transfectants showed significant responses upon addition of mMIP-3alpha. Murine MIP-3alpha RNA is expressed in thymus, small intestine and colon, whereas mCCR6 RNA is expressed in spleen and lymph nodes. RT-PCR an...
T-cell negative selection, a process by which intrathymic immunological tolerance is induced, involves the apoptosis-mediated clonal deletion of potentially autoreactive T cells. Although different experimental approaches suggest that this process is triggered as the result of activation-mediated cell death, the signal transduction pathways underly...
T-cell negative selection, a process by which intrathymic immunological tolerance is induced, involves the apoptosis-mediated clonal deletion of potentially autoreactive T cells. Although different experimental approaches suggest that this process is triggered as the result of activation-mediated cell death, the signal transduction pathways underly...
We have cloned the murine CCR6 receptor and its ligand, the β-chemokine mMIP-3α. Calcium mobilization assays performed with mCCR6 transfectants showed significant responses upon addition of mMIP-3α. Murine MIP-3α RNA is expressed in thymus, small intestine and colon, whereas mCCR6 RNA is expressed in spleen and lymph nodes. RT-PCR analysis of FACS-...
Mouse mammary tumor virus (MMTV) infects B lymphocytes and expresses a superantigen on the cell surface after integration of its reverse-transcribed genome. Superantigen-dependent B- and T-cell activation becomes detectable 2 to 3 days after infection. We show here that before this event, B cells undergo a polyclonal activation which does not invol...
Intrathymic expression of endogenous mouse mammary tumor virus (MMTV)-encoded superantigens (SAg) induces the clonal deletion of T cells bearing SAg-reactive T-cell receptor (TCR) Vbeta elements. However, the identity of the thymic antigen-presenting cells (APC) involved in the induction of SAg tolerance remains to be defined. We have analyzed the...
T cells bearing receptors with high affinity for self-antigens are responsible for the generation of autoimmune diseases. Therefore, potentially autoreactive thymocytes must be eliminated or inactived in normal individuals. Induction of tolerance in thymocytes occurs by a process of negative selection controlled by the thymic stroma, and in particu...
Tolerance against superantigens (SAgs) encoded by endogenous mouse mammary tumor virus (Mtv) loci involves the intrathymic deletion of SAg-reactive T cells expressing a particular TCR V beta-chain, presumably upon presentation of the SAg by specialized APC. However, although the role of dendritic cells (DC) in the induction of tolerance against con...
Are the dendritic cells (DC) found in the thymus similar in origin and function to those in other lymphoid tissues? Thymic DC are generally similar in morphological appearance to DC elsewhere, and share many cell surface markers. Thymic DC are shortlived cells which are, like DC elsewhere, of bone marrow origin1,2. However, it had not been clear wh...
The early thymus precursor population of adult mice has the capacity to generate T cells, B cells and dendritic cells (DC). These precursors were injected into the thymus of irradiated recipients in order to follow the kinetics of thymic DC development. The resultant cohort of T-lineage cells developing in the thymus was accompanied by a parallel c...
Mouse thymic dendritic cells (DC) have been isolated after collagenase digestion, selection of the low-density cell fraction, then depletion of T-lineage cells and other non-DC by treatment with specific monoclonal antibodies (mAb) and removal with anti-Ig-coated magnetic beads. The resulting DC preparation represented 0.1-0.2% of total thymic cell...
Rat thymic dendritic cells (DC) have been analyzed by flow cytometry in order to study the variations on the cell surface marker expression upon culture at 37°C. Our results demonstrates that whereas expression of major histocompatability complex (MHC) molecules, CD45, Mac-1, LFA-1, B-cell markers, macrophage markers and some T-cell markers (as CD2...
Rat thymic dendritic cells have been isolated by collagenase digestion, separation of the low-density cell fraction by centrifugation on metrizamide, and differential adherence. The resulting dendritic cell preparation had a purity of > 90%, and has been analysed by flow cytometry (FCM) using a large panel of monoclonal antibodies (mAb). Dendritic...
Dendritic cells, a minor cell population in lymphoid tissues, are specialized for presentation of antigenic peptides to T lymphocytes. Thymic dendritic cells are involved in the deletion of self-reactive T lymphocytes. Although all dendritic cells are ultimately of bone-marrow origin, it has not been clear whether thymic dendritic cells are produce...
Thymic dendritic cells (DC) are considered to be involved in negative selection of T cells leading to the acquisition of self-tolerance1,2, and many lines of evidence suggest that they may participate in the maturational process of thymocyte development3, in the clonal amplification of mature medullary thymocytes4, and in intrathymic presentation o...