DOCSLIB.ORG

Uva-DARE (Digital Academic Repository)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Uva-DARE (Digital Academic Repository) UvA-DARE (Digital Academic Repository) In vivo studies on the role of Adhesion-GPCR CD97 in immunity Veninga, H. Publication date 2010 Link to publication Citation for published version (APA): Veninga, H. (2010). In vivo studies on the role of Adhesion-GPCR CD97 in immunity. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:04 Oct 2021 CD55 regulates CD97 expression, granulopoietic activity, and anti- bacterial host defense Henrike Veninga,1 Robert M. Hoek,1 Alex F. de Vos,2 Alex M. de Bruin,1 Dennis Flierman,1 Feng-Qi An,3 Tom van der Poll,2 René A.W. van Lier,1 M. Edward Medof,3 and Jörg Hamann1 1Department of Experimental Immunology and 2Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam,5 The Netherlands, 3Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA Manuscript in preparation Thesis henrike_HV.indd 77 26-9-2010 22:08:06 Thesis henrike_HV.indd 78 26-9-2010 22:08:06 CD55 regulates CD97 expression and granulopoietic activity, ABSTRACT Next to its well-established activity in regulating complement activation, CD55 is a ligand of the Adhesion class G protein-coupled receptor CD97; however, the relevance of this interaction has remained elusive. We here show that leukocytes fromCd55 -/- mice expressed significantly increased levels of CD97 that normalized after transfer into wild-type mice due to contact with CD55 on both leukocytes and stromal cells. Moreover, mice lacking CD55 displayed granulocytosis with about two-fold more circulating granulocytes in the blood stream, the marginated pool, and the spleen. This granulocytosis was independent of increased complement activity and copied the phenotype previously found in CD97- deficient mice. Augmented numbers of Gr-1-positive cells in cell cycle in the bone marrow indicated a higher granulopoietic activity in mice lacking CD55 or CD97. Concomitant with the increase in blood granulocyte numbers, Cd55-/- mice challenged with the respiratory pathogen Streptococcus pneumoniae developed less bacteremia and died later after infection. Collectively, these data suggest that complement-independent interaction of CD55 with CD97 is functionally relevant and involved in granulocyte homeostasis and host defense. INTRODUCTION (GPCRs), abundantly expressed by virtually Decay-accelerating factor (CD55) is a glycosyl- all immune cells (16-21). Like all Adhesion- phosphatidyl-inositol (GPI)-anchored mole- GPCRs, CD97 is a two-subunit molecule cule on leukocytes, erythrocytes, and serum- consisting of an extracellular α subunit that exposed stromal cells that accelerates the is non-covalently associated with a seven- decay of the complement convertases transmembrane (TM7) β subunit.(18) The C3 and C5 (1). The importance of CD55 two subunits originate from autocatalytic for preventing endogenous cells from processing of the CD97 polypeptide in 5 unwanted complement activation is evident the endoplasmatic reticulum (22). At the from the phenotype of CD55-deficient mice N-terminus, CD97 possesses tandemly that develop exaggerated autoimmune arranged epidermal growth factor (EGF)- reactions in a variety of spontaneous and like domains of which the first two interact induced models (2-7). Furthermore, studies with the N-terminal complement control in Cd55-/- mice showed that complement protein (CCP) domains of CD55 (23,24). activation not only facilitates innate immune When overexpressed in vitro, CD97 can responses but also adaptive immunity facilitate adhesion of CD55-bearing cells (8-12). Next to the well-established (15,19,20,23). However, with 86 μM, the function as regulator of the complement affinity between CD97 and CD55 is low (24), cascade, CD55 is engaged in complement- and investigation of CD97-deficient mice independent processes and is hijacked by revealed no signs of impaired leukocyte several viral and bacterial pathogens to migration (25,26). Moreover, CD97 signaling promote cell adhesion and invasion (13,14). in response to CD55 binding could not be Furthermore, we demonstrated previously demonstrated (21), which was unexpected that CD55 is a binding partner of CD97 (15). for a TM7 receptor. To investigate whether CD97 is a member of the EGF-TM7 family of CD55 and CD97 interact in vivo and to explore Adhesion class G protein-coupled receptors possible physiological consequences of this 79 Thesis henrike_HV.indd 79 26-9-2010 22:08:06 CD55 regulates CD97 expression and granulopoietic activity, interaction, we studied the expression of a polyclonal goat antibody against the α CD97 on leukocytes as well as the size and chain of CD97 (R&D Systems, Wiesbaden, behavior of the granulocyte compartments Germany) and a rabbit polyclonal antibody in CD55-deficient mice. We found that CD97 against the β chain of CD97 (26). expression on leukocytes was constitutively For flow cytometry, CD97 antibodies downregulated by CD55. Moreover, CD55- were biotinylated in house and used in deficient mice, like mice that lack CD97, had combination with streptavidin-conjugated increased levels of circulating granulocytes, APC or PeCy7. In addition, FITC-, PE-, PerCP- which was due to a higher granulopoietic Cy5.5-, PeCy7-, APC-, or biotin-conjugated activity in the bone marrow. Finally, mice mAbs specific for CD3, CD11b, CD45.1, lacking CD55 were better protected against CD45.2, B220, F4/80, Gr-1, Ly6C, NK1.1 (all S. pneumoniae-induced pneumonia. To- eBioscience, San Diego, CA, USA) and Ly6G gether, our data prove cross-talk between (BD Biosciences, San Jose, CA, USA) were CD55 and the Adhesion-GPCR CD97 in vivo used. and indicate a role of this interaction in granulocyte homeostasis and host defense. Flow cytometry Peripheral blood was collected in heparin MATERIALS AND METHODS by heart puncture. Single cell suspensions of spleen were made by mashing the Mice organs through a 70-μm cell strainer. Bone Mice deficient for CD55 Cd55( -/-, synonym: marrow cells were harvested from dissected Daf1-/-) and CD97 (Cd97-/-) have been femurs by flushing the bone marrow plug generated previously by us (27,26). Mice with PBS/0.5% bovine serum albumin lacking the receptors for C3a (C3ar1-/-) and (BSA). Erythrocytes were lysed with a buffer -/- C5a (C5ar1 ) were kind gifts of Prof. Graig containing 155 mM NH4Cl, 10 mM KHCO3, Gerard (Harvard Medical School, Boston, and 1 mM EDTA in all these cell preparations. MA, USA) (28,29). Compound mice were 25 μl whole blood or 5 x 105 splenocytes or created by crossing Cd55-/- mice with Cd97-/-, bone marrow cells were used per staining. C3ar1-/-, and C5ar1-/- mice (10). All genetically Nonspecific binding of mAbs was blocked modified mice were back-crossed to C57BL/6 by adding 10% normal mouse serum and for at least eight generations. C57BL/6 1.25 μg/ml anti-CD16/32 (clone 2.4G2; BD wild-type mice were littermates or were Biosciences) together with the appropriately purchased from Charles River (Maastricht, diluted mAbs in PBS containing 0.5% BSA. The Netherlands). Congenic mice expressed Cells were incubated for 30 min at 4°C, Cd45.1 in the B6.SJL strain. All mice used in followed (where appropriate) by a second this study were matched for age and sex and incubation step with streptavidin-APC kept under specific pathogen-free conditions. or -PeCy7 (eBioscience). Flow cytometric Experiments were approved by the Animal analysis was performed using a FACSCalibur Ethics Committees of our institutions. or FACSCanto (BD Biosciences) and the FlowJo software package (Tree Star, Ashland, Immunological reagents OR, USA). Absolute numbers were calculated Native CD97 was detected with hamster on basis of total cell counts measured on mAbs against EGF domain 1 (clone 1B2), a CASY cell counter (Schärfe, Reutlingen, EGF domain 2 (clone 1A2), and the α chain Germany) or FACSCalibur multiplied by the downstream of EGF domain 3 (clone 1C3) percentage of cells positive for a specific (20,30). For Western blot analysis, we used marker, as measured by flow cytometry. 80 Thesis henrike_HV.indd 80 26-9-2010 22:08:06 CD55 regulates CD97 expression and granulopoietic activity, Western blot analysis Adoptive transfer Immune cells from spleen and blood were Spleens were harvested from congenic wild- isolated as described above and solubilized in type (Cd45.1) or Cd55-/- (Cd45.2) mice. Single a lysis buffer consisting of 2% Triton X-100 in cell suspensions were made as described PBS, supplemented with Complete Protease above under aseptic conditions in sterile Inhibitor Mix (Roche, Mannheim, Germany). PBS, and 25 x 106 congenic wild-type or Lysates were made by agitation on a nutator Cd55-/- cells were injected into the tail vein for 30 min at 4°C, after which insoluble of Cd55-/- or congenic wild-type recipient material was removed by centrifugation in mice, respectively. Blood and spleen from a microfuge at 16,100 x g for 15 min. The recipient mice were collected 24 h after resulting supernatant was used for SDS- the adoptive transfer and analyzed by PAGE. Approximately 3 x 106 cell equivalents flow cytometry for CD97 expression on were loaded on a protein gel and blotted to leukocytes.
Load more

Recommended publications
  • Edinburgh Research Explorer
    Edinburgh Research Explorer International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list Citation for published version: Davenport, AP, Alexander, SPH, Sharman, JL, Pawson, AJ, Benson, HE, Monaghan, AE, Liew, WC, Mpamhanga, CP, Bonner, TI, Neubig, RR, Pin, JP, Spedding, M & Harmar, AJ 2013, 'International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands', Pharmacological reviews, vol. 65, no. 3, pp. 967-86. https://doi.org/10.1124/pr.112.007179 Digital Object Identifier (DOI): 10.1124/pr.112.007179 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Pharmacological reviews Publisher Rights Statement: U.S. Government work not protected by U.S. copyright General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 1521-0081/65/3/967–986$25.00 http://dx.doi.org/10.1124/pr.112.007179 PHARMACOLOGICAL REVIEWS Pharmacol Rev 65:967–986, July 2013 U.S.
    [Show full text]
  • The 'C3ar Antagonist' SB290157 Is a Partial C5ar2 Agonist
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.01.232090; this version posted August 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The ‘C3aR antagonist’ SB290157 is a partial C5aR2 agonist Xaria X. Li1, Vinod Kumar1, John D. Lee1, Trent M. Woodruff1* 1School of Biomedical Sciences, The University of Queensland, St Lucia, 4072 Australia. * Correspondence: Prof. Trent M. Woodruff School of Biomedical Sciences, The University of Queensland, St Lucia, 4072 Australia. Ph: +61 7 3365 2924; Fax: +61 7 3365 1766; E-mail: [email protected] Keywords: Complement C3a, C3aR, SB290157, C5aR1, C5aR2 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.01.232090; this version posted August 3, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abbreviations used in this article: BRET, bioluminescence resonance energy transfer; BSA, bovine serum albumin; C3aR, C3a receptor C5aR1, C5a receptor 1; CHO-C3aR, Chinese hamster ovary cells stably expressing C3aR; CHO-C5aR1, Chinese hamster ovary cells stably expressing C5aR1; DMEM, Dulbecco's Modified Eagle's Medium; ERK1/2, extracellular signal-regulated kinase 1/2; FBS, foetal bovine serum; HEK293, human embryonic kidney 293 cells; HMDM, human monocyte-derived macrophage; i.p., intraperitoneal; i.v., intravenous; rhC5a, recombinant human C5a; RT, room temperature; S.E.M.
    [Show full text]
  • Neutrophil Chemoattractant Receptors in Health and Disease: Double-Edged Swords
    Cellular & Molecular Immunology www.nature.com/cmi REVIEW ARTICLE Neutrophil chemoattractant receptors in health and disease: double-edged swords Mieke Metzemaekers1, Mieke Gouwy1 and Paul Proost 1 Neutrophils are frontline cells of the innate immune system. These effector leukocytes are equipped with intriguing antimicrobial machinery and consequently display high cytotoxic potential. Accurate neutrophil recruitment is essential to combat microbes and to restore homeostasis, for inflammation modulation and resolution, wound healing and tissue repair. After fulfilling the appropriate effector functions, however, dampening neutrophil activation and infiltration is crucial to prevent damage to the host. In humans, chemoattractant molecules can be categorized into four biochemical families, i.e., chemotactic lipids, formyl peptides, complement anaphylatoxins and chemokines. They are critically involved in the tight regulation of neutrophil bone marrow storage and egress and in spatial and temporal neutrophil trafficking between organs. Chemoattractants function by activating dedicated heptahelical G protein-coupled receptors (GPCRs). In addition, emerging evidence suggests an important role for atypical chemoattractant receptors (ACKRs) that do not couple to G proteins in fine-tuning neutrophil migratory and functional responses. The expression levels of chemoattractant receptors are dependent on the level of neutrophil maturation and state of activation, with a pivotal modulatory role for the (inflammatory) environment. Here, we provide an overview
    [Show full text]
  • Investigation of the Underlying Hub Genes and Molexular Pathogensis in Gastric Cancer by Integrated Bioinformatic Analyses
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Investigation of the underlying hub genes and molexular pathogensis in gastric cancer by integrated bioinformatic analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The high mortality rate of gastric cancer (GC) is in part due to the absence of initial disclosure of its biomarkers. The recognition of important genes associated in GC is therefore recommended to advance clinical prognosis, diagnosis and and treatment outcomes. The current investigation used the microarray dataset GSE113255 RNA seq data from the Gene Expression Omnibus database to diagnose differentially expressed genes (DEGs). Pathway and gene ontology enrichment analyses were performed, and a proteinprotein interaction network, modules, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. Finally, validation of hub genes was performed. The 1008 DEGs identified consisted of 505 up regulated genes and 503 down regulated genes.
    [Show full text]
  • Regulation of Immune Cells by Eicosanoid Receptors
    Regulation of Immune Cells by Eicosanoid Receptors The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Kim, Nancy D., and Andrew D. Luster. 2007. “Regulation of Immune Cells by Eicosanoid Receptors.” The Scientific World Journal 7 (1): 1307-1328. doi:10.1100/tsw.2007.181. http://dx.doi.org/10.1100/ tsw.2007.181. Published Version doi:10.1100/tsw.2007.181 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37298366 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Review Article Special Issue: Eicosanoid Receptors and Inflammation TheScientificWorldJOURNAL (2007) 7, 1307–1328 ISSN 1537-744X; DOI 10.1100/tsw.2007.181 Regulation of Immune Cells by Eicosanoid Receptors Nancy D. Kim and Andrew D. Luster* Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston E-mail: [email protected] Received March 13, 2007; Revised June 14, 2007; Accepted July 2, 2007; Published September 1, 2007 Eicosanoids are potent, bioactive, lipid mediators that regulate important components of the immune response, including defense against infection, ischemia, and injury, as well as instigating and perpetuating autoimmune and inflammatory conditions. Although these lipids have numerous effects on diverse cell types and organs, a greater understanding of their specific effects on key players of the immune system has been gained in recent years through the characterization of individual eicosanoid receptors, the identification and development of specific receptor agonists and inhibitors, and the generation of mice genetically deficient in various eicosanoid receptors.
    [Show full text]
  • Complement Pathway Biomarkers and Age-Related Macular Degeneration
    Eye (2016) 30, 1–14 © 2016 Macmillan Publishers Limited All rights reserved 0950-222X/16 www.nature.com/eye 1 2,3 Complement pathway M Gemenetzi and AJ Lotery REVIEW biomarkers and age- related macular degeneration Abstract In the age-related macular degeneration accounts for 35% of all cases of late AMD and (AMD) ‘inflammation model’, local inflamma- 20% of legal blindness attributable to AMD,4,5 tion plus complement activation contributes to cannot be treated or prevented at the moment the pathogenesis and progression of the dis- and indeed may be increased by anti-VEGF ease. Multiple genetic associations have now therapy.6,7 been established correlating the risk of devel- In this review, we present and comment on opment or progression of AMD. Stratifying the response to both complement and non- patients by their AMD genetic profile may complement-based treatments, in relation to facilitate future AMD therapeutic trials result- complement pathway mechanisms and ing in meaningful clinical trial end points with complement gene regulation of these smaller sample sizes and study duration. mechanisms. We discuss current and potential – Eye (2016) 30, 1 14; doi:10.1038/eye.2015.203; treatments for both wet and dry AMD in relation published online 23 October 2015 to complement pathway pathogenetic 1Royal Eye Unit, Kingston mechanisms. Hospital NHS Foundation Trust, Kingston Upon Thames, UK Introduction The complement system Based on the pioneering work of Dr Judah The innate immune system is composed of 2Southampton Eye Unit, ‘ ’ Folkman, novel research into angiogenesis immunological effectors that provide robust, Southampton University Hospital, Southampton, UK generated the commercial development of drugs immediate, and nonspecific immune responses.
    [Show full text]
  • An Unexpected Role for the Anaphylatoxin C5a Receptor in Allergic Sensitization Bart N
    commentaries fied mice with minimal or no steady-state Phone: (314) 362-8834; Fax: (314) 362-8826; 7. Socolovsky, M., et al. 2001. Ineffective erythropoie- sis in Stat5a(–/–)5b(–/–) mice due to decreased sur- phenotype. In many ways these mice could E-mail: [email protected]. vival of early erythroblasts. Blood. 98:3261–3273. be viewed as models for otherwise normal 8. Zang, H., et al. 2001. The distal region and receptor adult humans who exhibit exaggerated or 1. Palis, J., and Segel, G.B. 1998. Developmental biol- tyrosines of the Epo receptor are non-essential for ogy of erythropoiesis. Blood Rev. 12:106–114. in vivo erythropoiesis. EMBO J. 20:3156–3166. unexpected responses to inflammation, 2. Obinata, M., and Yanai, N. 1999. Cellular and 9. D’Andrea, A.D., et al. 1991. The cytoplasmic region infectious agents, or cancer progression. molecular regulation of an erythropoietic induc- of the erythropoietin receptor contains nonover- As such, they have the potential to identify tive microenvironment (EIM). Cell Struct. Funct. lapping positive and negative growth-regulatory 24:171–179. and dissect regulatory pathways that influ- domains. Mol. Cell. Biol. 11:1980–1987. 3. Menon, M.P., et al. 2006. Signals for stress erythro- 10. Wagner, K.U., et al. 2000. Conditional deletion of the ence but do not cause disease. poiesis are integrated via an erythropoietin receptor– Bcl-x gene from erythroid cells results in hemolytic phosphotyrosine-343–Stat5 axis. J. Clin. Invest. anemia and profound splenomegaly. Development. Acknowledgments 116:683–694. doi:10.1172/JCI25227. 127:4949–4958. 4. Teglund, S., et al.
    [Show full text]
  • C5a Promotes the Proliferation of Human Nasopharyngeal Carcinoma Cells Through PCAF-Mediated STAT3 Acetylation
    2260 ONCOLOGY REPORTS 32: 2260-2266, 2014 C5a promotes the proliferation of human nasopharyngeal carcinoma cells through PCAF-mediated STAT3 acetylation KEMIN CAI1*, YI WAN2*, ZHIMIN WANG2*, YU WANG1*, XIAOJUN ZHAO1* and XUELI BAO1 1Department of Otorhinolaryngology Head and Neck Surgery, Taizhou People's Hospital, Taizhou, Jiangsu 225300; 2Department of Neurosurgery, Suzhou Kowloon Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Suzhou, Jiangsu 215021, P.R. China Received May 30, 2014; Accepted July 29, 2014 DOI: 10.3892/or.2014.3420 Abstract. The anaphylatoxin C5a is a chemoattractant that malignancies in Southern China and Southeast Asia with an can induce various inflammatory responsesin vivo via the C5a incidence rate of 20-30 cases per 100,000 individuals (3,4), receptor (C5aR). There is emerging evidence that C5a is gener- and is believed to be associated with EB virus infection (4,5). ated in the cancer microenvironment. However, the role of C5a However, its pathogenesis remains unclear. It is known that in human nasopharyngeal carcinoma (NPC) remains largely tumor development is a multistep process of cumulative unclear. Thus, the present study aimed to examine the direct genetic alterations that lead to cell autonomy. During this influence of C5a stimulation on the proliferation of human NPC process, inflammatory mechanisms are thought to play a cells and to identify the underlying molecular mechanisms. critical role (6,7). The effects of C5a stimulation on the proliferation of human Complement activation is believed to play a critical role NPC cells were studied in vitro, and P300/CBP-associated in inflammatory responses in vivo (8).
    [Show full text]
  • Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition
    Article Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition Graphical Abstract Authors Lei Wang, Dandan Yao, R.N.V. Krishna Deepak, ..., Weimin Gong, Zhiyi Wei, Cheng Zhang Correspondence [email protected] (Z.W.), [email protected] (C.Z.) In Brief Wang et al. reported crystal structures of antagonist-bound human CRTH2 as a new asthma drug target. Chemically diverse antagonists occupy a similar semi-occluded pocket with distinct binding modes. Structural analysis suggests a potential ligand entry port and an opposite charge attraction-facilitated binding process for the endogenous CRTH2 ligand prostaglandin D2. Highlights d Crystal structures of antagonist-bound human CRTH2 are solved d A well-structured N terminus covers ligand binding pocket d Conserved and divergent binding features of CRTH2 antagonists are revealed d A multiple-step binding process of prostaglandin D2 is proposed Wang et al., 2018, Molecular Cell 72, 48–59 October 4, 2018 ª 2018 Elsevier Inc. https://doi.org/10.1016/j.molcel.2018.08.009 Molecular Cell Article Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition Lei Wang,1,7 Dandan Yao,2,3,7 R.N.V. Krishna Deepak,4 Heng Liu,1 Qingpin Xiao,1,5 Hao Fan,4 Weimin Gong,2,6 Zhiyi Wei,5,* and Cheng Zhang1,8,* 1Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA 2Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 3University
    [Show full text]
  • Complement and Cancer—A Dysfunctional Relationship?
    antibodies Review Complement and Cancer—A Dysfunctional Relationship? Joshua M. Thurman *, Jennifer Laskowski and Raphael A. Nemenoff Division of Nephrology and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; [email protected] (J.L.); raphael.nemenoff@cuanschutz.edu (R.A.N.) * Correspondence: [email protected]; Tel.: +1-303-724-7584 Received: 11 August 2020; Accepted: 3 November 2020; Published: 5 November 2020 Abstract: Although it was long believed that the complement system helps the body to identify and remove transformed cells, it is now clear that complement activation contributes to carcinogenesis and can also help tumors to escape immune-elimination. Complement is activated by several different mechanisms in various types of cancer, and complement activation fragments have multiple different downstream effects on cancer cells and throughout the tumor microenvironment. Thus, the role of complement activation in tumor biology may vary among different types of cancer and over time within a single tumor. In multiple different pre-clinical models, however, complement activation has been shown to recruit immunosuppressive myeloid cells into the tumor microenvironment. These cells, in turn, suppress anti-tumor T cell immunity, enabling the tumor to grow. Based on extensive pre-clinical work, therapeutic complement inhibitors hold great promise as a new class of immunotherapy. A greater understanding of the role of complement in tumor biology will improve our ability to identify those patients most likely to benefit from this treatment and to rationally combine complement inhibitors with other cancer therapies. Keywords: complement; cancer; immunity; myeloid cells; therapeutics 1. Introduction It was long assumed that the complement cascade contributes to the immunosurveillance of cancers, helping the body to recognize and eliminate transformed cells.
    [Show full text]
  • A Novel Role for CD55 in Granulocyte Homeostasis and Anti-Bacterial Host Defense
    A Novel Role for CD55 in Granulocyte Homeostasis and Anti-Bacterial Host Defense Henrike Veninga1*, Robert M. Hoek1, Alex F. de Vos2, Alex M. de Bruin1, Feng-Qi An3, Tom van der Poll2, Rene´ A. W. van Lier1, M. Edward Medof3,Jo¨ rg Hamann1 1 Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 2 Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 3 Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America Abstract Background: In addition to its complement-regulating activity, CD55 is a ligand of the adhesion class G protein-coupled receptor CD97; however, the relevance of this interaction has remained elusive. We previously showed that mice lacking a functional CD97 gene have increased numbers of granulocytes. Methodology/Results: Here,wedemonstratethatCD55-deficientmicedisplay a comparable phenotype with about two-fold more circulating granulocytes in the blood stream, the marginated pool, and the spleen. This granulocytosis was independent of increased complement activity. Augmented numbers of Gr-1-positive cells in cell cycle in the bone marrow indicated a higher granulopoietic activity in mice lacking either CD55 or CD97. Concomitant with the increase in blood granulocyte numbers, Cd55-/- mice challenged with the respiratory pathogen Streptococcus pneumoniae developed less bacteremia and died later after infection. Conclusions: Collectively, these data suggest that complement-independent interaction of CD55 with CD97 is functionally relevant and involved in granulocyte homeostasis and host defense. Citation: Veninga H, Hoek RM, de Vos AF, de Bruin AM, An F-Q, et al. (2011) A Novel Role for CD55 in Granulocyte Homeostasis and Anti-Bacterial Host Defense.
    [Show full text]
  • CD System of Surface Molecules
    THE CD SYSTEM OF LEUKOCYTE APPENDIX 4A SURFACE MOLECULES Monoclonal Antibodies to Human Cell Surface Antigens APPENDIX 4A Alice Beare,1 Hannes Stockinger,2 Heddy Zola,1 and Ian Nicholson1 1Women’s and Children’s Health Research Institute, Women’s and Children’s Hospital, Adelaide, Australia 2Institute of Immunology, University of Vienna, Vienna ABSTRACT Many of the leukocyte cell surface molecules are known by “CD” numbers. In this Appendix, a short introduction describes the history and the use of CD nomenclature and provides a few key references to enable access to the wider literature. This is followed by a table that lists all human molecules with approved CD names, tabulating alternative names, key structural features, cellular expression, major known functions, and usefulness of the molecules or antibodies against them in research or clinical applications. Curr. Protoc. Immunol. 80:A.4A.1-A.4A.73. C 2008 by John Wiley & Sons, Inc. Keywords: CD nomenclature r HLDA r HCDM r leukocyte marker r human leukocyte differentiation r antigens INTRODUCTION During the last 25 years, large numbers of monoclonal antibodies (MAbs) have been pro- duced that have facilitated the purification and functional characterization of a plethora of leukocyte surface molecules. The antibodies have been even more useful as markers for cell populations, allowing the counting, separation, and functional study of numer- ous subsets of cells of the immune system. A series of international workshops were instrumental in coordinating this development through multi-laboratory “blind” studies of thousands of antibodies. These HLDA (Human Leukocyte Differentiation Antigens) Workshops have, up until now, defined 500 different entities and assigned them cluster of differentiation (CD) designations.
    [Show full text]