Showing papers on "Receptor published in 2007"

The Physiology of Glucagon-like Peptide 1

Abstract: Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in ...

Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand

Abstract: We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide) Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor We also expressed a Gi-coupled designer receptor in hippocampal neurons (hM4D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo

A flagellin-induced complex of the receptor FLS2 and BAK1 initiates plant defence

Abstract: Plants sense potential microbial invaders by using pattern-recognition receptors to recognize pathogen-associated molecular patterns (PAMPs). In Arabidopsis thaliana, the leucine-rich repeat receptor kinases flagellin-sensitive 2 (FLS2) (ref. 2) and elongation factor Tu receptor (EFR) (ref. 3) act as pattern-recognition receptors for the bacterial PAMPs flagellin and elongation factor Tu (EF-Tu) (ref. 5) and contribute to resistance against bacterial pathogens. Little is known about the molecular mechanisms that link receptor activation to intracellular signal transduction. Here we show that BAK1 (BRI1-associated receptor kinase 1), a leucine-rich repeat receptor-like kinase that has been reported to regulate the brassinosteroid receptor BRI1 (refs 6,7), is involved in signalling by FLS2 and EFR. Plants carrying bak1 mutations show normal flagellin binding but abnormal early and late flagellin-triggered responses, indicating that BAK1 acts as a positive regulator in signalling. The bak1-mutant plants also show a reduction in early, but not late, EF-Tu-triggered responses. The decrease in responses to PAMPs is not due to reduced sensitivity to brassinosteroids. We provide evidence that FLS2 and BAK1 form a complex in vivo, in a specific ligand-dependent manner, within the first minutes of stimulation with flagellin. Thus, BAK1 is not only associated with developmental regulation through the plant hormone receptor BRI1 (refs 6,7), but also has a functional role in PRR-dependent signalling, which initiates innate immunity.

Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE.

Abstract: Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.

Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock

Abstract: To identify new components that regulate the inflammatory cascade during sepsis, we characterized the functions of myeloid-related protein-8 (Mrp8, S100A8) and myeloid-related protein-14 (Mrp14, S100A9), two abundant cytoplasmic proteins of phagocytes. We now demonstrate that mice lacking Mrp8-Mrp14 complexes are protected from endotoxin-induced lethal shock and Escherichia coli–induced abdominal sepsis. Both proteins are released during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the active component that induces intracellular translocation of myeloid differentiation primary response protein 88 and activation of interleukin-1 receptor–associated kinase-1 and nuclear factor-κB, resulting in elevated expression of tumor necrosis factor-α (TNF-α). Using phagocytes expressing a nonfunctional Toll-like receptor 4 (TLR4), HEK293 cells transfected with TLR4, CD14 and MD2, and by surface plasmon resonance studies in vitro, we demonstrate that Mrp8 specifically interacts with the TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. Therefore Mrp8-Mrp14 complexes are new inflammatory components that amplify phagocyte activation during sepsis upstream of TNFα–dependent effects.

MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment

Abstract: The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G αi- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition. © 2007 Nature Publishing Group.

Modulatory Effects of 1,25-Dihydroxyvitamin D3 on Human B Cell Differentiation

Abstract: 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) can modulate immune responses, but whether it directly affects B cell function is unknown Patients with systemic lupus erythematosus, especially those with antinuclear Abs and increased disease activity, had decreased 1,25(OH)(2)D(3) levels, suggesting that vitamin D might play a role in regulating autoantibody production To address this, we examined the effects of 1,25(OH)(2)D(3) on B cell responses and found that it inhibited the ongoing proliferation of activated B cells and induced their apoptosis, whereas initial cell division was unimpeded The generation of plasma cells and postswitch memory B cells was significantly inhibited by 1,25(OH)(2)D(3), although the up-regulation of genetic programs involved in B cell differentiation was only modestly affected B cells expressed mRNAs for proteins involved in vitamin D activity, including 1 alpha-hydroxylase, 24-hydroxylase, and the vitamin D receptor, each of which was regulated by 1,25(OH)(2)D(3) and/or activation Importantly, 1,25(OH)(2)D(3) up-regulated the expression of p27, but not of p18 and p21, which may be important in regulating the proliferation of activated B cells and their subsequent differentiation These results indicate that 1,25(OH)(2)D(3) may play an important role in the maintenance of B cell homeostasis and that the correction of vitamin D deficiency may be useful in the treatment of B cell-mediated autoimmune disorders

Calcium signalling in lymphocyte activation and disease.

Abstract: Calcium signals in cells of the immune system participate in the regulation of cell differentiation, gene transcription and effector functions. An increase in intracellular levels of calcium ions (Ca2+) results from the engagement of immunoreceptors, such as the T-cell receptor, B-cell receptor and Fc receptors, as well as chemokine and co-stimulatory receptors. The major pathway that induces an increase in intracellular Ca2+ levels in lymphocytes is through store-operated calcium entry (SOCE) and calcium-release-activated calcium (CRAC) channels. This Review focuses on the role of Ca2+ signals in lymphocyte functions, the signalling pathways leading to Ca2+ influx, the function of the recently discovered regulators of Ca2+ influx (STIM and ORAI), and the relationship between Ca2+ signals and diseases of the immune system.

Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists.

Abstract: The identification of the antigen recognition receptors for innate immunity, most notably the Toll-like receptors, has sparked great interest in therapeutic manipulation of the innate immune system. Toll-like receptor agonists are being developed for the treatment of cancer, allergies and viral infections, and as adjuvants for potent new vaccines to prevent or treat cancer and infectious diseases. As recognition grows of the role of inappropriate Toll-like receptor stimulation in inflammation and autoimmunity, significant efforts have begun to develop antagonists to Toll-like receptors as well.

IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system

Abstract: ST2 is an IL-1 receptor family member with transmembrane (ST2L) and soluble (sST2) isoforms. sST2 is a mechanically induced cardiomyocyte protein, and serum sST2 levels predict outcome in patients with acute myocardial infarction or chronic heart failure. Recently, IL-33 was identified as a functional ligand of ST2L, allowing exploration of the role of ST2 in myocardium. We found that IL-33 was a biomechanically induced protein predominantly synthesized by cardiac fibroblasts. IL-33 markedly antagonized angiotensin II- and phenylephrine-induced cardiomyocyte hypertrophy. Although IL-33 activated NF-kappaB, it inhibited angiotensin II- and phenylephrine-induced phosphorylation of inhibitor of NF-kappa B alpha (I kappa B alpha) and NF-kappaB nuclear binding activity. sST2 blocked antihypertrophic effects of IL-33, indicating that sST2 functions in myocardium as a soluble decoy receptor. Following pressure overload by transverse aortic constriction (TAC), ST2(-/-) mice had more left ventricular hypertrophy, more chamber dilation, reduced fractional shortening, more fibrosis, and impaired survival compared with WT littermates. Furthermore, recombinant IL-33 treatment reduced hypertrophy and fibrosis and improved survival after TAC in WT mice, but not in ST2(-/-) littermates. Thus, IL-33/ST2 signaling is a mechanically activated, cardioprotective fibroblast-cardiomyocyte paracrine system, which we believe to be novel. IL-33 may have therapeutic potential for beneficially regulating the myocardial response to overload.

Purine and pyrimidine receptors

Abstract: Adenosine 5'-triphosphate (ATP), in addition to its intracellular roles, acts as an extracellular signalling molecule via a rich array of receptors, which have been cloned and characterised. P1 receptors are selective for adenosine, a breakdown product of ATP, produced after degradation by ectonucleotidases. Four subtypes have been identified, A(1), A(2A), A(2B) and A(3) receptors. P2 receptors are activated by purines and some subtypes also by pyrimidines. P2X receptors are ligand-gated ion channel receptors and seven subunits have been identified, which form both homomultimers and heteromultimers. P2Y receptors are G protein-coupled receptors, and eight subtypes have been cloned and characterised to date.

Identification of a key pathway required for the sterile inflammatory response triggered by dying cells

Abstract: Dying cells stimulate inflammation, and this response is thought to contribute to the pathogenesis of many diseases. Very little has been known, however, about how cell death triggers inflammation. We found here that the acute neutrophilic inflammatory response to cell injury requires the signaling protein myeloid differentiation primary response gene 88 (Myd88). Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor 2 (Tlr2) and Tlr4 and normal responses in mice lacking Tlr1, Tlr3, Tlr6, Tlr7, Tlr9, Tlr11 or the interleukin-18 receptor (IL-18R). However, mice lacking IL-1R showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL-1alpha, and IL-1R function was required on non-bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL-1R-Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggest that inhibiting the IL-1R-Myd88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.

The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching

Abstract: Delta-like 4 (Dll4) is a transmembrane ligand for Notch receptors that is expressed in arterial blood vessels and sprouting endothelial cells. Here we show that Dll4 regulates vessel branching during development by inhibiting endothelial tip cell formation. Heterozygous deletion of dll4 or pharmacological inhibition of Notch signaling using γ-secretase inhibitor revealed a striking vascular phenotype, with greatly increased numbers of filopodia-extending endothelial tip cells and increased expression of tip cell marker genes compared with controls. Filopodia extension in dll4+/− retinal vessels required the vascular growth factor VEGF and was inhibited when VEGF signaling was blocked. Although VEGF expression was not significantly altered in dll4+/− retinas, dll4+/− vessels showed increased expression of VEGF receptor 2 and decreased expression of VEGF receptor 1 compared with wild-type, suggesting they could be more responsive to VEGF stimulation. In addition, expression of dll4 in wild-type tip cells was itself decreased when VEGF signaling was blocked, indicating that dll4 may act downstream of VEGF as a “brake” on VEGF-mediated angiogenic sprouting. Taken together, these data reveal Dll4 as a negative regulator of vascular sprouting and vessel branching that is required for normal vascular network formation during development.

S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules

Abstract: Damage-associated molecular pattern (DAMP) molecules have been introduced as important proinflammatory factors of innate immunity. One example known for many years to be expressed in cells of myeloid origin are phagocytic S100 proteins, which mediate inflammatory responses and recruit inflammatory cells to sites of tissue damage. An emerging concept of pattern recognition involves the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including S100 proteins. S100A8, S100A9, and S100A12 are found at high concentrations in inflamed tissue, where neutrophils and monocytes belong to the most abundant cell types. They exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo. Although S100A12 binds to RAGE, at least part of the proinflammatory effects of the S100A8/S100A9 complex depend upon interaction with other receptors. Because of the divergent expression patterns, the absence of S100A12 in rodents, the different interaction partners described, and the specific intracellular and extracellular effects reported for these proteins, it is important to differentiate between distinct S100 proteins rather than subsuming them with the term "S100/calgranulins." Analyzing the molecular basis of the specific effects exhibited by these proteins in greater detail bears the potential to elucidate important mechanisms of innate immunity, to establish valid biomarkers of phagocytic inflammation, and eventually to reveal novel targets for innovative anti-inflammatory therapies.

NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo.

Abstract: Well-documented experimental evidence from both in vitro and in vivo models of stroke strongly supports the critical involvement of NMDA receptor-mediated excitotoxicity in neuronal damage after stroke. Despite this, the results of clinical trials testing NMDA receptor antagonists as neuroprotectants after stroke and brain trauma have been discouraging. Here, we report that in mature cortical cultures, activation of either synaptic or extrasynaptic NR2B-containing NMDA receptors results in excitotoxicity, increasing neuronal apoptosis. In contrast, activation of either synaptic or extrasynaptic NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action against both NMDA receptor-mediated and non-NMDA receptor-mediated neuronal damage. A similar opposing action of NR2B and NR2A in mediating cell death and cell survival was also observed in an in vivo rat model of focal ischemic stroke. Moreover, we found that blocking NR2B-mediated cell death was effective in reducing infarct volume only when the receptor antagonist was given before the onset of stroke and not 4.5 h after stroke. In great contrast, activation of NR2A-mediated cell survival signaling with administration of either glycine alone or in the presence of NR2B antagonist significantly attenuated ischemic brain damage even when delivered 4.5 h after stroke onset. Together, the present work provides a molecular basis for the dual roles of NMDA receptors in promoting neuronal survival and mediating neuronal damage and suggests that selective enhancement of NR2A-containing NMDA receptor activation with glycine may constitute a promising therapy for stroke.

Autonomic Innervation and Regulation of the Immune System (1987-2007)

Abstract: Since 1987, only a few neuroanatomical studies have been conducted to identify the origin of innervation for the immune system. These studies demonstrated that all primary and secondary immune organs receive a substantial sympathetic innervation from sympathetic postganglionic neurons. Neither the thymus nor spleen receive any sensory neural innervation; however, there is evidence that lymph nodes and bone marrow may be innervated by sensory neurons located in dorsal root ganglia. There is no neuroanatomical evidence for a parasympathetic or vagal nerve supply to any immune organ. Thus, the primary pathway for the neural regulation of immune function is provided by the sympathetic nervous system (SNS) and its main neurotransmitter, norepinephrine (NE). Activation of the SNS primarily inhibits the activity of cells associated with the innate immune system, while it either enhances or inhibits the activity of cells associated with the acquired/adaptive immune system. Innate immune cells express both alpha and beta-adrenergic receptor subtypes, while T and B lymphocytes express adrenergic receptors of the beta2 subtype exclusively, except for murine Th2 cells that lack expression of any subtype. Via these adrenergic receptors, NE is able to regulate the level of immune cell activity by initiating a change in the level of cellular activity, which often involves a change in the level of gene expression for cytokines and antibodies.

Nuclear Activity of MLA Immune Receptors Links Isolate-Specific and Basal Disease-Resistance Responses

Abstract: Plant immune responses are triggered by pattern recognition receptors that detect conserved pathogen-associated molecular patterns (PAMPs) or by resistance (R) proteins recognizing isolate-specific pathogen effectors. We show that in barley, intracellular mildew A (MLA) R proteins function in the nucleus to confer resistance against the powdery mildew fungus. Recognition of the fungal avirulence A10 effector by MLA10 induces nuclear associations between receptor and WRKY transcription factors. The identified WRKY proteins act as repressors of PAMP-triggered basal defense. MLA appears to interfere with the WRKY repressor function, thereby de-repressing PAMP-triggered basal defense. Our findings reveal a mechanism by which these polymorphic immune receptors integrate distinct pathogen signals.

UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis

Abstract: Microglia, brain immune cells, engage in the clearance of dead cells or dangerous debris, which is crucial to the maintenance of brain functions. When a neighbouring cell is injured, microglia move rapidly towards it or extend a process to engulf the injured cell. Because cells release or leak ATP when they are stimulated or injured, extracellular nucleotides are thought to be involved in these events. In fact, ATP triggers a dynamic change in the motility of microglia in vitro and in vivo, a previously unrecognized mechanism underlying microglial chemotaxis; in contrast, microglial phagocytosis has received only limited attention. Here we show that microglia express the metabotropic P2Y6 receptor whose activation by endogenous agonist UDP triggers microglial phagocytosis. UDP facilitated the uptake of microspheres in a P2Y6-receptor-dependent manner, which was mimicked by the leakage of endogenous UDP when hippocampal neurons were damaged by kainic acid in vivo and in vitro. In addition, systemic administration of kainic acid in rats resulted in neuronal cell death in the hippocampal CA1 and CA3 regions, where increases in messenger RNA encoding P2Y6 receptors that colocalized with activated microglia were observed. Thus, the P2Y6 receptor is upregulated when neurons are damaged, and could function as a sensor for phagocytosis by sensing diffusible UDP signals, which is a previously unknown pathophysiological function of P2 receptors in microglia.

Regulation of Receptor Trafficking by GRKs and Arrestins

Abstract: To ensure that extracellular stimuli are translated into intracellular signals of appropriate magnitude and specificity, most signaling cascades are tightly regulated. One of the major mechanisms involved in the regulation of G protein-coupled receptors (GPCRs) involves their endocytic trafficking. GPCR endocytic trafficking entails the targeting of receptors to discrete endocytic sites at the plasma membrane, followed by receptor internalization and intracellular sorting. This regulates the level of cell surface receptors, the sorting of receptors to degradative or recycling pathways, and in some cases the specific signaling pathways. In this chapter we discuss the mechanisms that regulate receptor endocytic trafficking, emphasizing the role of GPCR kinases (GRKs) and arrestins in this process.

Role of Receptors in Bacillus thuringiensis Crystal Toxin Activity

Abstract: Bacillus thuringiensis produces crystalline protein inclusions with insecticidal or nematocidal properties. These crystal (Cry) proteins determine a particular strain's toxicity profile. Transgenic crops expressing one or more recombinant Cry toxins have become agriculturally important. Individual Cry toxins are usually toxic to only a few species within an order, and receptors on midgut epithelial cells have been shown to be critical determinants of Cry specificity. The best characterized of these receptors have been identified for lepidopterans, and two major receptor classes have emerged: the aminopeptidase N (APN) receptors and the cadherin-like receptors. Currently, 38 different APNs have been reported for 12 different lepidopterans. Each APN belongs to one of five groups that have unique structural features and Cry-binding properties. While 17 different APNs have been reported to bind to Cry toxins, only 2 have been shown to mediate toxin susceptibly in vivo. In contrast, several cadherin-like proteins bind to Cry toxins and confer toxin susceptibility in vitro, and disruption of the cadherin gene has been associated with toxin resistance. Nonetheless, only a small subset of the lepidopteran-specific Cry toxins has been shown to interact with cadherin-like proteins. This review analyzes the interactions between Cry toxins and their receptors, focusing on the identification and validation of receptors, the molecular basis for receptor recognition, the role of the receptor in resistant insects, and proposed models to explain the sequence of events at the cell surface by which receptor binding leads to cell death.

Adenosine, an endogenous distress signal, modulates tissue damage and repair

Abstract: Adenosine is formed inside cells or on their surface, mostly by breakdown of adenine nucleotides. The formation of adenosine increases in different conditions of stress and distress. Adenosine acts on four G-protein coupled receptors: two of them, A(1) and A(3), are primarily coupled to G(i) family G proteins; and two of them, A(2A) and A(2B), are mostly coupled to G(s) like G proteins. These receptors are antagonized by xanthines including caffeine. Via these receptors it affects many cells and organs, usually having a cytoprotective function. Joel Linden recently grouped these protective effects into four general modes of action: increased oxygen supply/demand ratio, preconditioning, anti-inflammatory effects and stimulation of angiogenesis. This review will briefly summarize what is known and what is not in this regard. It is argued that drugs targeting adenosine receptors might be useful adjuncts in many therapeutic approaches.

Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro

Abstract: Background and purpose: A nonpsychoactive constituent of the cannabis plant, cannabidiol has been demonstrated to have low affinity for both cannabinoid CB1 and CB2 receptors. We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors. This study aimed to investigate whether these properties of cannabidiol extend to CB1 receptors expressed in mouse brain and to human CB2 receptors that have been transfected into CHO cells.

Structure and Function of Toll Receptors and Their Ligands

Abstract: The Toll family of class I transmembrane receptors recognizes and responds to diverse structures associated with pathogenic microorganisms. These receptors mediate initial responses in innate immunity and are required for the development of the adaptive immune response. Toll receptor signaling pathways are also implicated in serious autoimmune diseases such as endotoxic shock and thus are important therapeutic targets. In this review we discuss how microbial structures as different as nucleic acids and lipoproteins can be recognized by the extracellular domains of Toll receptors. We review recent evidence that the mechanism of signal transduction is complex and involves sequential changes in the conformation of the receptor induced by binding of the ligand. Finally, we assess the emerging area of cross talk in the Toll pathways. Recent work suggests that signaling through TLR4 in response to endotoxin is modified by inputs from at least two other pathways acting through beta2 integrins and protein kinase Cepsilon.

Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7

Abstract: Chemotactic cytokines (chemokines) attract immune cells, although their original evolutionary role may relate more closely with embryonic development. We noted differential expression of the chemokine receptor CXCR7 (RDC-1) on marginal zone B cells, a cell type associated with autoimmune diseases. We generated Cxcr7−/− mice but found that CXCR7 deficiency had little effect on B cell composition. However, most Cxcr7−/− mice died at birth with ventricular septal defects and semilunar heart valve malformation. Conditional deletion of Cxcr7 in endothelium, using Tie2-Cre transgenic mice, recapitulated this phenotype. Gene profiling of Cxcr7−/− heart valve leaflets revealed a defect in the expression of factors essential for valve formation, vessel protection, or endothelial cell growth and survival. We confirmed that the principal chemokine ligand for CXCR7 was CXCL12/SDF-1, which also binds CXCR4. CXCL12 did not induce signaling through CXCR7; however, CXCR7 formed functional heterodimers with CXCR4 and enhanced CXCL12-induced signaling. Our results reveal a specialized role for CXCR7 in endothelial biology and valve development and highlight the distinct developmental role of evolutionary conserved chemokine receptors such as CXCR7 and CXCR4.