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Antal Rot

Publications and source records attributed to Antal Rot.

14 recordsLinked to original sources
PubMed2005

Chemokine receptor CXCR4-dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells.

Regulation of the availability of chemokine SDF-1 (CXCL12) in bone marrow is still not fully understood. Here we describe a unique function for the chemokine receptor CXCR4 expressed on bone marrow endothelial cells, which efficiently internalize circulating SDF-1, resulting in its translocation into the bone marrow. Translocated SDF-1 increased the homing of transplanted human CD34(+) hematopoietic progenitors to the bone marrow. The chemokine transporter function of CXCR4 was a characteristic of endothelial and stromal cells but not of hematopoietic cells. Thus, chemokine translocation across the blood-bone marrow barrier allows effective transfer of functional SDF-1 from the periphery to the stem cell niche in the bone marrow during both homeostasis and 'alarm' situations.

Animals↗
PubMed2005

Contribution of Duffy antigen to chemokine function.

In addition to classical G protein-coupled receptors (GPCRs), a group of alternative, "silent" chemokine receptors has recently been identified. These serpentine molecules are not coupled to G proteins and subsequent signaling cascades, but can efficiently internalize their cognate chemokine ligands, thus act as "interceptors" (internalizing receptors). Here we discuss a mechanism by which a member of this family, Duffy antigen (DARC), contributes to chemokine-induced leukocyte emigration. Cumulative experimental evidence suggests that DARC on venular endothelium mediates chemokine internalization at the abluminal surface followed by transcytosis and transfer of the chemokine cargo onto the luminal surface. DARC is also expressed on the erythrocyte surface of DARC positive individuals. Erythrocyte DARC binds plasma chemokines which results, on one hand, in impediment of the chemokines loss from the circulation and, on the other hand, in neutralization of chemokines in the blood. This leads to leukocyte protection from inadvertent "desensitization" and enhancement of leukocyte recruitment.

Animals↗
PubMed2005

The chemokine receptor D6 limits the inflammatory response in vivo.

How the inflammatory response is initiated has been well defined but relatively little is known about how such responses are resolved. Here we show that the D6 chemokine receptor is involved in the post-inflammatory clearance of beta-chemokines from cutaneous sites. After induction of inflammation by phorbol esters, wild-type mice showed a transient inflammatory response. However, in D6-deficient mice, an excess concentration of residual chemokines caused a notable inflammatory pathology with similarities to human psoriasis. These results suggest that D6 is involved in the resolution of the cutaneous inflammatory response.

Animals↗
PubMed2004

Plasmacytoid dendritic cell recruitment by immobilized CXCR3 ligands.

Plasmacytoid dendritic cells (pDCs) recognize microbes, viruses in particular, and provide unique means of innate defense against them. The mechanism of pDC tissue recruitment remained enigmatic because the ligands of CXCR3, the cardinal chemokine receptor on pDCs, have failed to induce in vitro chemotaxis of pDCs in the absence of additional chemokines. In this study, we demonstrate that CXCR3 is sufficient to induce pDC migration, however, by a migratory mechanism that amalgamates the features of haptotaxis and chemorepulsion. To mediate "haptorepulsion" of pDCs, CXCR3 requires the encounter of its cognate ligands immobilized, optimally by heparan sulfate, in a form of a negative gradient. This is the first report of the absolute requirement of chemokine immobilization and presentation for its in vitro promigratory activity. The paradigmatic example of pDC haptorepulsion described here may represent a new pathophysiologically relevant migratory mechanism potentially used by other cells in response to other chemokines.

Antigen Presentation↗
PubMed2004

The chemokine receptor D6 constitutively traffics to and from the cell surface to internalize and degrade chemokines.

The D6 heptahelical membrane protein, expressed by lymphatic endothelial cells, is able to bind with high affinity to multiple proinflammatory CC chemokines. However, this binding does not allow D6 to couple to the signaling pathways activated by typical chemokine receptors such as CC-chemokine receptor-5 (CCR5). Here, we show that D6, like CCR5, can rapidly internalize chemokines. However, D6-internalized chemokines are more effectively retained intracellularly because they more readily dissociate from the receptor during vesicle acidification. These chemokines are then degraded while the receptor recycles to the cell surface. Interestingly, D6-mediated chemokine internalization occurs without bringing about a reduction in cell surface D6 levels. This is possible because unlike CCR5, D6 is predominantly localized in recycling endosomes capable of trafficking to and from the cell surface in the absence of ligand. When chemokine is present, it can enter the cells associated with D6 already destined for internalization. By this mechanism, D6 can target chemokines for degradation without the necessity for cell signaling, and without desensitizing the cell to subsequent chemokine exposure.

Adaptor Proteins, Vesicular Transport↗
PubMed2004

Platelet-released supernatants increase migration and proliferation, and decrease osteogenic differentiation of bone marrow-derived mesenchymal progenitor cells under in vitro conditions.

Platelet-rich plasma is currently promoted to serve as an adjuvant for bone grafts to enhance quantity and quality of newly forming bone; however, the underlying cellular mechanisms are not fully understood. We show here that supernatants of leukocyte-depleted thrombin-activated platelets increase migration and proliferation, and decrease osteogenic differentiation of bone marrow-derived mesenchymal progenitor cells under in vitro conditions. Using neutralizing antibodies raised against platelet-derived growth factor (PDGF), the observed effects of platelet-released supernatants were diminished. The mitogenic response was also decreased when extracellular signal-regulated protein kinase (ERK) signalling was inhibited by PD98059; however, PD98059 did not reverse the effects of platelet-released supernatants on migration and osteogenic differentiation. Consistent with an ERK-mediated mitogenic activity, incubation of serum-starved mesenchymal cell progenitors with platelet-released supernatants increased phosphorylation of the kinase. Together, these observations indicate that PDGF is a key factor released upon platelet activation that can increase migration and proliferation, and decreases osteogenic differentiation of mesenchymal progenitor cells under in vitro conditions. The results further suggest that ERK signalling is required to mediate the mitogenic response to platelet-released supernatants.

Adult↗
PubMed2004

Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells.

Chemokines compose a sophisticated communication system used by all our cell types, including immune cells. Chemokine messages are decoded by specific receptors that initiate signal transduction events leading to a multitude of cellular responses, leukocyte chemotaxis and adhesion in particular. Critical determinants of the in vivo activities of chemokines in the immune system include their presentation by endothelial cells and extracellular matrix molecules, as well as their cellular uptake via "silent" chemokine receptors (interceptors) leading either to their transcytosis or to degradation. These regulatory mechanisms of chemokine histotopography, as well as the promiscuous and overlapping receptor specificities of inflammation-induced chemokines, shape innate responses to infections and tissue damage. Conversely, the specific patterns of homeostatic chemokines, where each chemokine is perceived by a single receptor, are charting lymphocyte navigation routes for immune surveillance. This review presents our current understanding of the mechanisms that regulate the cellular perception and pathophysiologic meaning of chemokines.

Animals↗
PubMed2003

Chemokines on the move: control by the chemokine "interceptors" Duffy blood group antigen and D6.

Chemokines drive and direct leukocyte trafficking across the biological barriers. Controlling the microanatomical localization and quantity of chemokines is of fundamental importance in regulating these migratory responses. Here we discuss the emerging roles that two atypical chemokine receptors, Duffy antigen and D6, may play in controlling chemokine movement and how this may impinge on chemokine function. Mechanistically, Duffy antigen and D6 represent a subclass of chemokine internalizing receptors, "interceptors," taking chemokines into nucleated cells in the apparent absence of signaling. The subsequent fate of chemokines, either transport or degradation, may ultimately depend on cell type-specific targeting within the endocytotic pathway.

Animals↗
PubMed2003

In situ binding assay for studying chemokine interactions with endothelial cells.

The association of chemokines with endothelial cells (EC) and extracellular matrices is required for the prototypical pro-emigratory and pro-migratory in vivo activity of these molecules, respectively. In order to investigate chemokine binding to intact microanatomical structures, e.g. venular EC, we have developed an in situ binding assay. This is an autoradiographic morphological method in which the saturable binding of radiolabeled chemokines is studied in vitro in pieces of viable tissues. This article discusses the general applicability, advantages and shortcomings of the in situ binding assay in comparison with the other techniques available for visualizing chemokine receptor binding by cells in the tissues. We used this assay to demonstrate: (a) selective specific binding of CXC and CC chemokines to the EC of postcapillary venules but not capillaries or arteries; (b) selective specific binding of CC chemokines to the EC of afferent lymphatic vessels; and (c) selective specific binding of inflammatory chemokines to the EC lining high endothelial venules (HEV) in lymph nodes. The assessment of ligand cross-competition provided a fingerprint of chemokine-binding specificity of the EC in each of these microanatomical sites. This fingerprint could be paralleled with the chemokine-binding profiles of two non-signaling chemokine-binding molecules, Duffy antigen receptor for chemokines (DARC) and D6, present in venular and lymphatic EC, respectively. These observations allowed us to put forward the hypotheses regarding the involvement of EC DARC and D6 in chemokine transport and presentation by the EC.

Animals↗
PubMed2002

Targeting CLA/E-selectin interactions prevents CCR4-mediated recruitment of human Th2 memory cells to human skin in vivo.

Naive Th cells, bearing receptors for cutaneous antigens, become activated in skin-draining lymph nodes and express cutaneous lymphocyte antigen (CLA), which confers to these cells the capacity to migrate into the skin to exert their normal effector functions. In the case of atopic dermatitis (AD), allergen-specific Th2 cells generate exacerbated responses and induce skin inflammation. In such a situation, interfering with the specific mechanism of skin homing would provide a therapeutic benefit. Here we report that CLA+ Th2 memory cells, derived from skin lesions of AD patients, selectively migrate to human skin grafts transplanted onto SCID mice in response to CCR4 but not CCR3, CCR8 or CXCR3 ligands. Skin homing of human CCR4+ Th2 memory cells was Pertussis toxin sensitive and restricted to the CLA+ subset. Furthermore, treatment of these mice with anti-E-selectin monoclonal antibody was sufficient to prevent CCL22-mediated Th2 cell migration to human skin, which both, validates the model and highlights the importance of CLA/E-selectin interactions in the homing process of Th2 cells to the skin. Using this mechanistic model we demonstrate that skin homing of human Th2 memory cells can be efficiently suppressed using a low molecular weight E-selectin antagonist, which is of clinical relevance for the treatment of inflammatory skin diseases, including AD.

Adult↗
PubMed2002

Overexpression of IL-4 alters the homeostasis in the skin.

IL-4 has been implicated to play an important role in the pathogenesis of many inflammatory diseases including skin diseases such as atopic dermatitis. Because it is not clear which pathologic features of atopic dermatitis are dependent on IL-4, we assessed the consequences of IL-4 overexpression in the skin, using transgenic mice overexpressing IL-4 ubiquitously. Although transgenic mice display no clinical signs of skin inflammation, IL-4 induced a wide spectrum of pathologies including an increased number of mast cells and Langerhans cells in dermis and epidermis, respectively, focal deposition of collagen and a considerably reduced adipocyte layer in the dermis as well as an increased mitotic activity of keratinocytes, reflected in acanthosis and hyperkeratosis. The increase in Langerhans cell number may be explained in part by the substantially reduced Langerhans cell emigration from the epidermis in transgenic mice. The molecular mechanism behind this phenomenon remains to be clarified. Under in vitro culture conditions, Langerhans cells from transgenic mice undergo a maturation process similar to that of Langerhans cells from control mice, and their immunostimulatory capacity is also comparable. In contrast, transgenic Langerhans cells are superior to control Langerhans cells in their antigen-processing capacity. We conclude that the overexpression of IL-4 in the skin is, by itself, not sufficient for the induction of a full-blown atopic dermatitis phenotype, but several changes seen in the skin of transgenic mice mirror the cardinal pathologic manifestations of this disease.

Adipocytes↗
PubMed1996

Inflammatory and Physiological Roles of Chemokines.

Chemokines, members of the family of chemotactic peptides, have a well documented function in different inflammatory diseases where they induce leukocyte emigration into lesions. Several recent observations indicate that, in addition to pathological states, chemokines are also produced and secreted under physiological conditions by various exocrine glands in amounts sufficient for their full biological effect. The glands involved in chemokine production and secretion include eccrine sweat glands, lactating mammary glands, lacrimal and salivary glands. It is suggested that analogous to their role in inflammatory diseases, chemokines produced by the exocrine glands are responsible for the induction of homeostatic leukocyte migration into mucosal epithelia and skin and also, mammary glands and milk. In addition, the mechanism by which chemokines induce leukocyte homing under physiological circumstances is discussed.

Journal Article↗