The Experts below are selected from a list of 205704 Experts worldwide ranked by ideXlab platform
A. Neil Barclay - One of the best experts on this subject based on the ideXlab platform.
-
Dissection of Agonistic and Blocking Effects of CD200 Receptor Antibodies
PLOS ONE, 2013Co-Authors: Munir Akkaya, Marie-laure Aknin, Billur Akkaya, A. Neil BarclayAbstract:The CD200 Receptor (CD200R) is present mainly on myeloid cells and gives inhibitory signals when engaged by its ligand CD200. The interaction is currently of therapeutic interest in cancer and inflammation. However functional effects are complicated by the fact that CD200R is itself polymorphic and also a member of a paired Receptor family with four closely related gene products in mice called CD200RLa etc. We show that a second allele of CD200R (termed CD200R(2)) that differs in 7 amino acids also binds CD200 but did not react with the widely used CD200R antibody OX110. Biochemical and functional analysis showed that the CD200/CD200R interaction was blocked by the OX131, mAb that recognises both CD200R(1) and CD200R(2), but not by OX110 mAb. Both mAb can give agonistic inhibitory signals but functional analysis shows OX131 mAb also has the potential to block inhibition by preventing the ligand-Receptor interaction and hence gives opposing effects. Although OX131 mAb cross-reacts with the activating Receptor CD200RLe, it is specific for CD200R in C57BL/6 whilst OX110 mAb cross-reacts on CD200RLc. The results show the importance of the repertoire of paired Receptors in strains or individuals and mAb used with implications for paired Receptor analysis and therapeutics.
-
Structures of CD200/CD200 Receptor Family and Implications for Topology, Regulation, and Evolution
Structure, 2013Co-Authors: Deborah Hatherley, Susan M. Lea, Steven Johnson, A. Neil BarclayAbstract:CD200 is a widely distributed membrane glycoprotein that regulates myeloid cell activity through its interaction with an inhibitory Receptor (CD200R). The interaction is of interest as a target for treating excessive inflammation and for treating leukemia. There are closely related proteins to CD200R that give activating signals making this a “paired Receptor.” We report X-ray crystallography structures for the inhibitory CD200R, the activating Receptor CD200RLa, and a complex between CD200R and CD200. Both CD200 and CD200R contain two Ig-like domains and interact through their NH2 terminal domains compatible with immunological synapse-like interactions occurring between myeloid cells and other CD200-expressing cells. The failure of the activating Receptor to bind CD200 resides in subtle changes around the interface. CD200 has been acquired by herpes viruses to mimic the host interaction. CD200R has evolved rapidly presumably driven by pathogen pressure but it may also be important in homeostasis through interactions with commensal bacteria.
-
Essential Roles for Dok2 and RasGAP in CD200 Receptor-Mediated Regulation of Human Myeloid Cells
Journal of Immunology, 2009Co-Authors: Robin Mihrshahi, A. Neil Barclay, Marion H. BrownAbstract:The CD200 Receptor (CD200R) acts as a negative regulator of myeloid cells by interacting with its widely expressed ligand CD200. Using mutants expressed in U937 cells, we show that inhibition is mediated by the PTB domain binding motif (NPLY) in the Receptor’s cytoplasmic region. The adaptor protein downstream of tyrosine kinase 2 (Dok2) bound directly to the phosphorylated NPLY motif with a 10-fold higher affinity (KD of ∼1 μM at 37°C) than the closely related Dok1. Both of these proteins have been suggested to play a role in CD200R signaling in murine cells. Dok2 was phosphorylated in response to CD200R engagement and recruited RAS p21 protein activator 1 (RasGAP). Knockdown of Dok2 and RasGAP by RNA interference revealed that these proteins are required for CD200R signaling, while knockdown of Dok1 and the inositol 5-phosphatase SHIP did not affect CD200R-mediated inhibition. We conclude that CD200R inhibits the activation of human myeloid cells through direct recruitment of Dok2 and subsequent activation of RasGAP, which distinguishes this Receptor from the majority of inhibitory Receptors that utilize ITIMs and recruit phosphatases.
-
A critical function for CD200 in lung immune homeostasis and the severity of influenza infection.
Nature Immunology, 2008Co-Authors: Robert J. Snelgrove, Jonathon D Sedgwick, A. Neil Barclay, John Goulding, Arnaud Didierlaurent, Daphne Lyonga, Seema Vekaria, Lorna Edwards, Emily Gwyer, Tracy HussellAbstract:The lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways. We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 Receptor (CD200R) than did their systemic counterparts. Lung macrophages were restrained by CD200 expressed on airway epithelium. Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death. The administration of agonists that bind CD200R, however, prevented inflammatory lung disease. Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection.
-
Recombinant CD200 Protein Does Not Bind Activating Proteins Closely Related to CD200 Receptor
Journal of Immunology, 2005Co-Authors: Deborah Hatherley, Holly Cherwinski, Mehrdad Moshref, A. Neil BarclayAbstract:CD200 (OX2) is a cell surface glycoprotein that interacts with a structurally related Receptor (CD200R) expressed mainly on myeloid cells and is involved in regulation of macrophage and mast cell function. In mouse there are up to five genes related to CD200R with conflicting data as to whether they bind CD200. We show that mouse CD200 binds the inhibitory Receptor CD200R with a comparable affinity (Kd = 4 microM) to those found for the rat and human CD200 CD200R interactions. CD200 gave negligible binding to the activating Receptors, CD200RLa, CD200RLb, and CD200RLc, by direct analysis at the protein level using recombinant monomeric and dimeric fusion proteins or to CD200RLa and CD200RLb when expressed at the cell surface. An additional potential activating gene, CD200RLe, found in only some mouse strains also did not bind CD200. Thus, the CD200 Receptor family consists of both activatory and inhibitory members like several other paired ligand Receptors, such as signal regulatory protein, killer cell Ig-like Receptor/KAR, LY49, dendritic cell immunoReceptor/dendritic cell immunoactivating Receptor, and paired Ig-like type 2 Receptor. Although the ligand for the inhibitory product is a widely distributed host protein, the ligands of the activating forms remain to be identified, and one possibility is that they are pathogen components.
Andrew D Dick - One of the best experts on this subject based on the ideXlab platform.
-
Systemic and local anti‐C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis
Clinical and Experimental Immunology, 2009Co-Authors: David A. Copland, Andrew D Dick, K. Hussain, Sivasankar Baalasubramanian, Timothy Hughes, Bryan Paul Morgan, Lindsay B. NicholsonAbstract:Activation of complement occurs during autoimmune retinal and intraocular inflammatory disease as well as neuroretinal degenerative disorders. The cleavage of C5 into fragments C5a and C5b is a critical event during the complement cascade. C5a is a potent proinflammatory anaphylatoxin capable of inducing cell migration, adhesion and cytokine release, while membrane attack complex C5b-9 causes cell lysis. Therapeutic approaches to prevent complement-induced inflammation include the use of blocking monoclonal antibodies (mAb) to prevent C5 cleavage. In these current experiments, the rat anti-mouse C5 mAb (BB5·1) was utilized to investigate the effects of inhibition of C5 cleavage on disease progression and severity in experimental autoimmune uveoretinitis (EAU), a model of organ-specific autoimmunity in the eye characterized by structural retinal damage mediated by infiltrating macrophages. Systemic treatment with BB5·1 results in significantly reduced disease scores compared with control groups, while local administration results in an earlier resolution of disease. In vitro, contemporaneous C5a and interferon-g signalling enhanced nitric oxide production, accompanied by down-regulation of the inhibitory myeloid CD200 Receptor, contributing to cell activation. These experiments demonstrate that C5 cleavage contributes to the full expression of EAU, and that selective C5 blockade via systemic and local routes of administration can suppress disease. This presents great therapeutic potential to protect against tissue damage during autoimmune responses in the retina or inflammation-induced degenerative disease.
-
Blocking CD200-CD200 Receptor axis augments NOS-2 expression and aggravates experimental autoimmune uveoretinitis in Lewis rats.
Ocular Immunology and Inflammation, 2009Co-Authors: Debatri Banerjee, Andrew D DickAbstract:Purpose: Tissue expression of CD200 generates inhibitory or down-regulatory signals to macrophages and microglia within CNS and retina. Our interests were to investigate whether blocking CD200 Receptor (CD200R) signalling in vivo results in macrophage activation and thus aggravation of EAU in Lewis rats. Methods: Retinal extract-immunised Lewis rats were treated day 3 and 5 post-immunisation with CD200R mAb or normal mouse serum. Phenotypic analysis of the leucocyte infiltrate and disease severity was clinically and histogically examined. Results: Rats administered with CD200R mAb developed earlier onset of EAU and more severe disease. Blocking CD200R increased retinal neuronal CD200 expression and, although disease severity was increased concomitant with an increase in NOS-2 expression, retinal macrophage numbers were not increased. Conclusions: Contemporaneous with data from CD200KO mice, these results support the notion that CD200-CD200R signalling suppresses macrophage activation. Exacerbation of EAU ...
-
CD200 maintains microglial potential to migrate in adult human retinal explant model.
Current Eye Research, 2009Co-Authors: D A Carter, Andrew D DickAbstract:Purpose. Retinal microglia (MG) migrate in response to injury, degeneration and inflammation dependent upon both soluble and cognate signals they receive. Previously we found that lipopolysaccharide/interferon-γ (LPS/IFNγ) stimulation induces a paradoxical IL-10 mediated suppression of MG migration from retinal explants. Given the high expression of neuronal CD200, which can induce down regulation of CD200 Receptor-positive MG activation and neuronal fractalkine expression potentially stimulating MG migration, we wished to further examine their respective roles in the maintenance of MG activation and migration. Methods. A human retinal explant model of MG migration was used. CD200 Receptor and fractalkine Receptor stimulation was achieved by addition to explants of CD200:Fc fusion protein and recombinant cytokine respectively, with or without LPS-IFNγ stimulation that is known to suppress migration. Cell migration and cell activation (iNOS expression) was counted and assessed by numbers of CD45+ cells by ...
-
Monoclonal Antibody-Mediated CD200 Receptor Signaling Suppresses Macrophage Activation and Tissue Damage in Experimental Autoimmune Uveoretinitis
American Journal of Pathology, 2007Co-Authors: David A. Copland, Jonathon D Sedgwick, Holly Cherwinski, Maria C. Jenmalm, Joseph H. Phillips, Claudia J. Calder, Ben J. E. Raveney, Lindsay B. Nicholson, Andrew D DickAbstract:Macrophage responses are regulated by multiple secreted factors as well as by cell surface Receptors, including the inhibitory signals resulting from ligation of myeloid CD200 Receptors (CD200R) by the widely distributed CD200. In the absence of CD200, animals display increased susceptibility to autoimmunity and earlier onset aggressive autoimmune disease. In these current experiments, an agonist monoclonal rat anti-mouse CD200R (DX109) antibody delivered a negative signal to bone marrow-derived macrophages, which suppressed interferon (IFN)γ-mediated nitric oxide (NO) and interleukin-6 production. Experimental autoimmune uveoretinitis (EAU) was used as a model of organ-specific autoimmunity in the eye, a tissue with extensive neuronal and endothelial CD200 expression. In mice lacking CD200 (CD200−/−), increased numbers of retina-infiltrating macrophages displaying heightened NO responses were observed during EAU. In addition, we aimed to suppress disease by maintaining tonic suppression of macrophage activation via CD200R. Systemically administered DX109 monoclonal antibody suppressed EAU despite maintained T-cell proliferation and IFNγ production. Furthermore, locally administered DX109 monoclonal antibody resulted in an earlier resolution of disease. These experiments demonstrate that promoting CD200R-mediated signaling can successfully prevent full expression of IFNγ-mediated macrophage activation and protect against tissue damage during autoimmune responses.
-
Enhanced Tolerance to Autoimmune Uveitis in CD200-Deficient Mice Correlates with a Pronounced Th2 Switch in Response to Antigen Challenge
Journal of Immunology, 2004Co-Authors: Neil Taylor, Jonathon D Sedgwick, Andrew D Dick, Claudia J. Calder, Karen Mcconnachie, R. Dawson, Janet LiversidgeAbstract:A single exposure to inhaled Ag 10 days before immunization leads to long term, Ag-specific tolerance. Respiratory tract myeloid APCs are implicated, but how regulation is invoked, and how tolerance is sustained are unclear. This study examines the in vivo function of the myeloid regulatory molecule CD200 in the process of tolerance induction. Despite earlier onset of experimental autoimmune uveitis in sham-tolerized, CD200-deficient mice, disease incidence and subsequent severity were actually reduced compared with those in wild-type mice. Protection was more effective and long term, lasting at least 28 days. Halting disease progression and tolerance in CD200−/− mice correlated with a marked increase in Th2-associated cytokine production by Ag-challenged splenocytes. Reduced overall disease and enhanced tolerance in the CD200-deficient mice in this model system were unexpected and may be related to altered populations of MHC class IIlow APC in the respiratory tract compared with wild-type mice together with associated activation of STAT6 in draining lymph nodes of tolerized mice. These data indicate that in the absence of default inhibitory CD200 Receptor signaling, alternative, powerful regulatory mechanisms are invoked. This may represent either permissive dominant Th2 activation or an altered hierarchy of negative signaling by other myeloid cell-expressed regulatory molecules.
Jonathon D Sedgwick - One of the best experts on this subject based on the ideXlab platform.
-
A critical function for CD200 in lung immune homeostasis and the severity of influenza infection.
Nature Immunology, 2008Co-Authors: Robert J. Snelgrove, Jonathon D Sedgwick, A. Neil Barclay, John Goulding, Arnaud Didierlaurent, Daphne Lyonga, Seema Vekaria, Lorna Edwards, Emily Gwyer, Tracy HussellAbstract:The lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways. We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 Receptor (CD200R) than did their systemic counterparts. Lung macrophages were restrained by CD200 expressed on airway epithelium. Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death. The administration of agonists that bind CD200R, however, prevented inflammatory lung disease. Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection.
-
Monoclonal Antibody-Mediated CD200 Receptor Signaling Suppresses Macrophage Activation and Tissue Damage in Experimental Autoimmune Uveoretinitis
American Journal of Pathology, 2007Co-Authors: David A. Copland, Jonathon D Sedgwick, Holly Cherwinski, Maria C. Jenmalm, Joseph H. Phillips, Claudia J. Calder, Ben J. E. Raveney, Lindsay B. Nicholson, Andrew D DickAbstract:Macrophage responses are regulated by multiple secreted factors as well as by cell surface Receptors, including the inhibitory signals resulting from ligation of myeloid CD200 Receptors (CD200R) by the widely distributed CD200. In the absence of CD200, animals display increased susceptibility to autoimmunity and earlier onset aggressive autoimmune disease. In these current experiments, an agonist monoclonal rat anti-mouse CD200R (DX109) antibody delivered a negative signal to bone marrow-derived macrophages, which suppressed interferon (IFN)γ-mediated nitric oxide (NO) and interleukin-6 production. Experimental autoimmune uveoretinitis (EAU) was used as a model of organ-specific autoimmunity in the eye, a tissue with extensive neuronal and endothelial CD200 expression. In mice lacking CD200 (CD200−/−), increased numbers of retina-infiltrating macrophages displaying heightened NO responses were observed during EAU. In addition, we aimed to suppress disease by maintaining tonic suppression of macrophage activation via CD200R. Systemically administered DX109 monoclonal antibody suppressed EAU despite maintained T-cell proliferation and IFNγ production. Furthermore, locally administered DX109 monoclonal antibody resulted in an earlier resolution of disease. These experiments demonstrate that promoting CD200R-mediated signaling can successfully prevent full expression of IFNγ-mediated macrophage activation and protect against tissue damage during autoimmune responses.
-
Regulation of microglial cell responses in murine Toxoplasma encephalitis by CD200/CD200 Receptor interaction
Acta Neuropathologica, 2006Co-Authors: Martina Deckert, Jonathon D Sedgwick, Elena Fischer, Dirk SchlüterAbstract:Under autoimmune inflammatory conditions within the brain, evidence suggests that neurons downregulate microglial activation through CD200/CD200R interaction, which reduces disease severity. To gain insight into the regulation of intracerebral immune reactions by resident brain cells in chronic cerebral infections, the expression of the CD200 antigen and the CD200R as well as the functional role of CD200/CD200R interactions were characterized in murine Toxoplasma encephalitis. In the normal brain of C57BL/6 wild type mice, CD200 was ubiquitously expressed on neurons, their axons, cerebral endothelial cells, and plexus macrophages. CD200R was expressed at very low levels on cerebral macrophages and microglia without differences between CD200^−/− and wild type mice. Infection of C57BL/6 mice with Toxoplasma gondii induced an upregulation of CD200R on microglia and of CD200 on blood vessel endothelial cells. In Toxoplasma encephalitis of CD200^−/− mice, microglial cell numbers strongly increased due to an enhanced proliferation indicated by increased Ki-67 immunoreactivity. In addition, microglial activation was increased in CD200^−/− mice as evidenced by a further upregulation of already high MHC class II levels as well as an increased expression of the anti-parasitic effector molecules, TNF and iNOS. The increased microglial cell activation resulted in a reduced intracerebral parasite burden and an increased survival rate. Thus, in Toxoplasma encephalitis, microglial activity was regulated via CD200/CD200R-mediated interaction further pointing to an intrinsic regulation of brain resident cells under inflammatory CNS conditions.
-
regulation of microglial cell responses in murine toxoplasma encephalitis by CD200 CD200 Receptor interaction
Acta Neuropathologica, 2006Co-Authors: Martina Deckert, Jonathon D Sedgwick, Elena Fischer, Dirk SchlüterAbstract:Under autoimmune inflammatory conditions within the brain, evidence suggests that neurons downregulate microglial activation through CD200/CD200R interaction, which reduces disease severity. To gain insight into the regulation of intracerebral immune reactions by resident brain cells in chronic cerebral infections, the expression of the CD200 antigen and the CD200R as well as the functional role of CD200/CD200R interactions were characterized in murine Toxoplasma encephalitis. In the normal brain of C57BL/6 wild type mice, CD200 was ubiquitously expressed on neurons, their axons, cerebral endothelial cells, and plexus macrophages. CD200R was expressed at very low levels on cerebral macrophages and microglia without differences between CD200−/− and wild type mice. Infection of C57BL/6 mice with Toxoplasma gondii induced an upregulation of CD200R on microglia and of CD200 on blood vessel endothelial cells. In Toxoplasma encephalitis of CD200−/− mice, microglial cell numbers strongly increased due to an enhanced proliferation indicated by increased Ki-67 immunoreactivity. In addition, microglial activation was increased in CD200−/− mice as evidenced by a further upregulation of already high MHC class II levels as well as an increased expression of the anti-parasitic effector molecules, TNF and iNOS. The increased microglial cell activation resulted in a reduced intracerebral parasite burden and an increased survival rate. Thus, in Toxoplasma encephalitis, microglial activity was regulated via CD200/CD200R-mediated interaction further pointing to an intrinsic regulation of brain resident cells under inflammatory CNS conditions.
-
Regulation of Myeloid Cell Function through the CD200 Receptor
Journal of Immunology, 2005Co-Authors: Maria C. Jenmalm, Holly Cherwinski, Edward P. Bowman, Joseph H. Phillips, Jonathon D SedgwickAbstract:Myeloid cells play pivotal roles in chronic inflammatory diseases through their broad proinflammatory, destructive, and remodeling capacities. CD200 is widely expressed on a variety of cell types, while the recently identified CD200R is expressed on myeloid cells and T cells. CD200 deletion in vivo results in myeloid cell dysregulation and enhanced susceptibility to autoimmune inflammation, suggesting that the CD200-CD200R interaction is involved in immune suppression. We demonstrate in this study that CD200R agonists suppress mouse and human myeloid cell function in vitro, and also define a dose relationship between Receptor expression and cellular inhibition. IFN-γ- and IL-17-stimulated cytokine secretion from mouse peritoneal macrophages was inhibited by CD200R engagement. Inhibitory effects were not universal, as LPS-stimulated responses were unaffected. Inhibition of U937 cell cytokine production correlated with CD200R expression levels, and inhibition was only observed in low CD200R expressing cells, if the CD200R agonists were further cross-linked. Tetanus toxoid-induced human PBMC IL-5 and IL-13 secretion was inhibited by CD200R agonists. This inhibition was dependent upon cross-linking the CD200R on monocytes, but not on cross-linking the CD200R on CD4 + T cells. In all, we provide direct evidence that the CD200-CD200R interaction controls monocyte/macrophage function in both murine and human systems, further supporting the potential clinical application of CD200R agonists for the treatment of chronic inflammatory diseases.
Linde Meyaard - One of the best experts on this subject based on the ideXlab platform.
-
CD200R1L is a functional evolutionary conserved activating Receptor in human neutrophils.
Journal of leukocyte biology, 2021Co-Authors: M Inês Pascoal Ramos, Linde Meyaard, Geertje H A Westerlaken, Nikolaos Satravelas, Can Keşmir, Jorn E. Stok, Ruben J. Geerdink, Michiel Van Der VlistAbstract:Inhibitory and activating immune Receptors play a key role in modulating the amplitude and duration of immune responses during infection and in maintaining immune balance in homeostatic conditions. The CD200 Receptor (CD200R) gene family in humans encodes one inhibitory Receptor, CD200R1, and one putative activating member, CD200R1 Like (CD200R1L). It is demonstrated that CD200R1L is endogenously expressed by human neutrophils and activates cellular functions such as reactive oxygen species (ROS) production via Syk, PI3Kβ, PI3Kδ, and Rac GTPase signaling. Phylogenetic analysis shows that CD200R1L is present in many species among vertebrates, ranging from birds to primates, suggesting that evolutionary conservation of this Receptor is critical for protection against co-evolving pathogens. The duplication event that generated CD200R1L from CD200R occurred several times throughout evolution, supporting convergent evolution of CD200R1L. In our phylogenetic trees, CD200R1L has longer branch lengths than CD200R1 in most species, suggesting that CD200R1L is evolving faster than CD200R1. It is proposed that CD200R1L represents a hitherto uncharacterized activating Receptor on human neutrophils.
-
Identification of a novel conserved signaling motif in CD200 Receptor required for its inhibitory function.
PloS one, 2021Co-Authors: Laura Timmerman, Linde Meyaard, J Fréderique De Graaf, Nikolaos Satravelas, Can Keşmir, Michiel Van Der VlistAbstract:The inhibitory signaling of CD200 Receptor 1 (CD200R) has been attributed to its NPxY signaling motif. However, NPxY-motifs are present in multiple protein families and are mostly known to mediate protein trafficking between subcellular locations rather than signaling. Therefore, we investigated whether additional motifs specify the inhibitory function of CD200R. We performed phylogenetic analysis of the intracellular domain of CD200R in mammals, birds, bony fish, amphibians and reptiles. Indeed, the tyrosine of the NPxY-motif is fully conserved across species, in line with its central role in CD200R signaling. In contrast, P295 of the NPxY-motif is not conserved. Instead, a conserved stretch of negatively charged amino acids, EEDE279, and two conserved residues P285 and K292 in the flanking region prior to the NPxY-motif are required for CD200R mediated inhibition of p-Erk, p-Akt308, p-Akt473, p-rpS6 and LPS-induced IL-8 secretion. Altogether, we show that instead of the more common NPxY-motif, CD200R signaling can be assigned to a unique signaling motif in mammals defined by: EEDExxPYxxYxxKxNxxY.
-
Identification of a novel conserved signaling motif in CD200 Receptor required for its inhibitory function
2020Co-Authors: Laura Timmerman, Linde Meyaard, J Fréderique De Graaf, Nikolaos Satravelas, Can Keşmir, Michiel Van Der VlistAbstract:The inhibitory signaling of CD200 Receptor 1 (CD200R) has been attributed to its NPxY signaling motif, which upon phosphorylation recruits Dok2 and subsequently RasGAP. We performed phylogenetic analysis of the intracellular domain of CD200R in mammals, birds, bony fish, amphibians and reptiles. We found that the tyrosine of the NPxY-motif is fully conserved across species, in line with its central role in CD200R signaling. However, in other proteins the NPxY-motif is better known for its role in protein trafficking between subcellular locations rather than signaling. Therefore, we propose that in addition to the NPxY-motif, there are more residues or motifs that contribute to CD200R signaling. Indeed, the conservation of the intracellular tail of CD200R is not limited to the NPxY-motif. We demonstrate that an additional conserved stretch of negatively charged amino acids, EEDE279, and the conserved residues P285 and K292 in the flanking region prior to the NPxY-motif are required for CD200R mediated inhibition of p-Erk, p-Akt308, p-Akt473, p-rpS6 and LPS-induced IL-8 secretion. We thereby propose that P295 of the NPxY-motif is not important for CD200R function, changing the signaling motif to an NxxY-motif. Altogether, we show that in addition to the NxxY-motif, CD200R signaling requires a highly conserved motif of negatively charged amino acids and two highly conserved residues to inhibit PI3K/Akt and MAPK/Erk signaling. This extends the CD200R signaling motif to a unique motif in mammals: EEDExxPYxxYxxKxNxxY.
-
Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain
bioRxiv, 2020Co-Authors: Ramin Raoof, Michiel Van Der Vlist, Hanneke L.d.m. Willemen, Judith Prado, Sabine Versteeg, Martijn Vos, Roeland Lockhorst, R. Jeroen Pasterkamp, William Khoury-hanold, Linde MeyaardAbstract:Abstract The current paradigm states that inflammatory pain passively resolves following the cessation of the inflammatory insult. Yet, in a substantial proportion of patients with inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, spontaneous or treatment-induced resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain1–5. Mechanistic insight as how inflammatory pain is resolved is lacking. Here we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. To resolve pain, macrophages transfer mitochondria to sensory neurons. This transfer requires expression of CD200 Receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain and suggests a new direction for treatment of chronic pain. Graphical Abstract
-
The pro-tumor effect of CD200 expression is not mimicked by agonistic CD200R antibodies.
PLOS ONE, 2019Co-Authors: Zofia Pilch, Linde Meyaard, Louis Boon, Katarzyna Tonecka, Marcin Skorzynski, Zuzanna Sas, Agata Braniewska, Tomasz Kryczka, Jakub Golab, Tomasz P. RygielAbstract:Tumor-infiltrating immune cells can impact tumor growth and progression. The inhibitory CD200 Receptor (CD200R) suppresses the activation of myeloid cells and lack of this pathway results in a reduction of tumor growth, conversely a tumorigenic effect of CD200R triggering was also described. Here we investigated the role of CD200R activation in syngeneic mouse tumor models. We showed that agonistic CD200R antibody reached tumors, but had no significant impact on tumor growth and minor effect on infiltration of immune myeloid cells. These effects were reproduced using two different anti-CD200R clones. In contrast, we showed that CD200-deficiency did decrease melanoma tumor burden. The presence of either endogenous or tumor-expressed CD200 restored the growth of metastatic melanoma foci. On the basis of these findings, we conclude that blockade of the endogenous ligand CD200 prevented the tumorigenic effect of CD200R-expressing myeloid cells in the tumor microenvironment, whereas agonistic anti-CD200R has no effect on tumor development.
Janet Liversidge - One of the best experts on this subject based on the ideXlab platform.
-
Is the CD200/CD200 Receptor interaction more than just a myeloid cell inhibitory signal?
Critical Reviews in Immunology, 2006Co-Authors: Konstantinos Minas, Janet LiversidgeAbstract:The membrane glycoprotein CD200, which has a widespread but defined distribution and a structurally similar Receptor (CD200R) that transmits an inhibitory signal to cells of the hematopoetic lineage, especially myeloid cells, has been characterized. CD200R expression is restricted predominantly to cells of the myeloid lineage indicating that this ligand/Receptor pair has a specific role in controlling myeloid cell function. In addition to CD200R, several related genes have been identified. Whether these gene products also regulate immune function is controversial. CD200R is also expressed by certain subsets of T cells and CD200 may be expressed by antigen-presenting cells, adding additional layers of complexity to the CD200/CD200R axis. Because monocytic myeloid cells provide a link between the innate and adaptive immune response, mechanisms to control their function through Receptors such as CD200R will have therapeutic potential. Regulation of immune responses is accomplished by the concerted, but opposing, activity of kinases and phosphatases, fine control often being achieved through paired Receptors. In this review, we will consider whether CD200R signaling functions within a framework of paired activating and inhibitory Receptors and whether the inhibitory signal delivered has functional consequences beyond inhibition of myeloid cell proinflammatory activation.
-
is the CD200 CD200 Receptor interaction more than just a myeloid cell inhibitory signal
Critical Reviews in Immunology, 2006Co-Authors: Konstantinos Minas, Janet LiversidgeAbstract:The membrane glycoprotein CD200, which has a widespread but defined distribution and a structurally similar Receptor (CD200R) that transmits an inhibitory signal to cells of the hematopoetic lineage, especially myeloid cells, has been characterized. CD200R expression is restricted predominantly to cells of the myeloid lineage indicating that this ligand/Receptor pair has a specific role in controlling myeloid cell function. In addition to CD200R, several related genes have been identified. Whether these gene products also regulate immune function is controversial. CD200R is also expressed by certain subsets of T cells and CD200 may be expressed by antigen-presenting cells, adding additional layers of complexity to the CD200/CD200R axis. Because monocytic myeloid cells provide a link between the innate and adaptive immune response, mechanisms to control their function through Receptors such as CD200R will have therapeutic potential. Regulation of immune responses is accomplished by the concerted, but opposing, activity of kinases and phosphatases, fine control often being achieved through paired Receptors. In this review, we will consider whether CD200R signaling functions within a framework of paired activating and inhibitory Receptors and whether the inhibitory signal delivered has functional consequences beyond inhibition of myeloid cell proinflammatory activation.
-
Enhanced Tolerance to Autoimmune Uveitis in CD200-Deficient Mice Correlates with a Pronounced Th2 Switch in Response to Antigen Challenge
Journal of Immunology, 2004Co-Authors: Neil Taylor, Jonathon D Sedgwick, Andrew D Dick, Claudia J. Calder, Karen Mcconnachie, R. Dawson, Janet LiversidgeAbstract:A single exposure to inhaled Ag 10 days before immunization leads to long term, Ag-specific tolerance. Respiratory tract myeloid APCs are implicated, but how regulation is invoked, and how tolerance is sustained are unclear. This study examines the in vivo function of the myeloid regulatory molecule CD200 in the process of tolerance induction. Despite earlier onset of experimental autoimmune uveitis in sham-tolerized, CD200-deficient mice, disease incidence and subsequent severity were actually reduced compared with those in wild-type mice. Protection was more effective and long term, lasting at least 28 days. Halting disease progression and tolerance in CD200−/− mice correlated with a marked increase in Th2-associated cytokine production by Ag-challenged splenocytes. Reduced overall disease and enhanced tolerance in the CD200-deficient mice in this model system were unexpected and may be related to altered populations of MHC class IIlow APC in the respiratory tract compared with wild-type mice together with associated activation of STAT6 in draining lymph nodes of tolerized mice. These data indicate that in the absence of default inhibitory CD200 Receptor signaling, alternative, powerful regulatory mechanisms are invoked. This may represent either permissive dominant Th2 activation or an altered hierarchy of negative signaling by other myeloid cell-expressed regulatory molecules.
-
Control of myeloid activity during retinal inflammation
Journal of Leukocyte Biology, 2003Co-Authors: Andrew D Dick, Cathryn Broderick, Eh Hughes, Morag Robertson, John V Forrester, D A Carter, Janet LiversidgeAbstract:Combating myeloid cell-mediated de- struction of the retina during inflammation or neu- rodegeneration is dependent on the integrity of homeostatic mechanisms within the tissue that may suppress T cell activation and their subsequent cy- tokine responses, modulate infiltrating macro- phage activation, and facilitate healthy tissue re- pair. Success is dependent on response of the res- ident myeloid-cell populations (microglia (MG)) to activation signals, commonly cytokines, and the control of infiltrating macrophage activation dur- ing inflammation, both of which appear highly pro- grammed in normal and inflamed retina. The evi- dence that tissue CD200 constitutively provides down-regulatory signals to myeloid-derived cells via cognate CD200-CD200 Receptor (R) interac- tion supports inherent tissue control of myeloid cell activation. In the retina, there is extensive neuronal and endothelial expression of CD200. Retinal MG in CD200 knockout mice display nor- mal morphology but unlike the wild-type mice, are present in increased numbers and express nitric oxide synthase 2, a macrophage activation marker, inferring that loss of CD200 or absent CD200R ligation results in "classical" activation of myeloid cells. Thus, when mice lack CD200, they show increased susceptibility to and accelerated onset of tissue-specific autoimmunity. J. Leukoc. Biol. 74: 000-000; 2003.
-
Control of myeloid activity during retinal inflammation
Journal of Leukocyte Biology, 2003Co-Authors: Andrew D Dick, Eh Hughes, Morag Robertson, John V Forrester, D A Carter, Cathryn A. Broderick, Janet LiversidgeAbstract:Combating myeloid cell-mediated destruction of the retina during inflammation or neurodegeneration is dependent on the integrity of homeostatic mechanisms within the tissue that may suppress T cell activation and their subsequent cytokine responses, modulate infiltrating macrophage activation, and facilitate healthy tissue repair. Success is dependent on response of the resident myeloid-cell populations [microglia (MG)] to activation signals, commonly cytokines, and the control of infiltrating macrophage activation during inflammation, both of which appear highly programmed in normal and inflamed retina. The evidence that tissue CD200 constitutively provides down-regulatory signals to myeloid-derived cells via cognate CD200-CD200 Receptor (R) interaction supports inherent tissue control of myeloid cell activation. In the retina, there is extensive neuronal and endothelial expression of CD200. Retinal MG in CD200 knockout mice display normal morphology but unlike the wild-type mice, are present in increased numbers and express nitric oxide synthase 2, a macrophage activation marker, inferring that loss of CD200 or absent CD200R ligation results in "classical" activation of myeloid cells. Thus, when mice lack CD200, they show increased susceptibility to and accelerated onset of tissue-specific autoimmunity.