Zaal, A.

English

Dendritic cells (DCs) and the complement system are two essential parts of our immune system, that are both involved in pathogen recognition and elimination. Increased levels of both DCs and complement activation products are observed during infection and in several autoimmune diseases, indicating that crosstalk between these two arms of innate immunity is likely to occur. Until recently, however, data on the interplay between complement and DC activation, especially in humans, is limited. The potential use of complement interfering compounds for treatment of several diseases, emphasizing the importance of understanding the effect of complement on DC activation. In this thesis, we aim to clarify the effect of C5aR and TLR crosstalk on the activation of human DCs. C5a reduced the production of TLR-induced pro-inflammatory cytokines by DCs. IL-10 induction upon accelerated TLR-induced ERK/p38-CREB1 signaling was demonstrated to be key in the regulatory effect of C5a on pro-inflammatory cytokine production. In line with these findings, C5a-priming of DCs reduced T cell responses. RNA sequencing analyses demonstrated that C5aR and TLR crosstalk in addition induces a core regulatory network in DCs. In the absence of a TLR stimulus, C5a specifically inhibited Fc-gamma receptor mediated uptake of immune complexes. Overall, we discovered a potential regulatory role of C5a in human DC activation, which may especially be of importance to prevent the development of autoimmunity and to regulate inflammation during bacterial infections. The use of C5/C5a interfering drugs should, therefore, be considered with extreme care

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)UvA-DARE (Digital Academic Repository)C5aR and TLR crosstalkRegulatory effect of anaphylatoxin C5a on human dendritic cellsZaal, A.Publication date2018Document VersionOther versionLicenseOtherLink to publicationCitation for published version (APA):Zaal, A. (2018). C5aR and TLR crosstalk: Regulatory effect of anaphylatoxin C5a on humandendritic cells. [Thesis, externally prepared, Universiteit van Amsterdam].General rightsIt 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 opencontent license (like Creative Commons).Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.Download date:09 Mar 2023C5aR	and	TLRAnouk	ZaalCrosstalk:Regulatory	effect	ofanaphylatoxin	C5a	onhuman	dendritic	cellsLPS C5aexpressionC5aR crosstalkTLR4DCsproductioncomplementinduced cellsslanDCsmoDCsgenesimmunecell geneaffectedcytokine C5aR1C5aR2ICs p38 absenceTNFdiseaseCD1cIRF4slanTh1h17 function MSKviaCD4PCRhumansIFNeffectvitroclusterATF3PRRsinfectionsproteinculturelevelsCD14TLR7APCpresencenetworksenrichedimDCsCD11cIL12BSGK1IL10cooperativenormalizedR848contrastligandscontrolstimulipCREB1beforeSPHK1SPADEPI3KβmoredataMDC8RSK2�lowTLRsMDC1TRIFFOXOGIPRC5L2CD3homeostasisrecognizeuntreated stimulusproducesynergylocallydonorsnovelMyD88C5aRAGPCRslargelesspDCsMDC2skinS1PPam3csk4humansUITNODIGINGVoor het bijwonen van de openbare verdediging  van mijn proefschrift:C5aR and TLR Crosstalk: Regulatory effect of anaphylatoxin C5a on human dendritic cells   Op donderdag  22 februari 2018 om 10:00 uur  in de Agnietenkapel Oudezijds  Voorburgwal 229-231AmsterdamAansluitend bent u van harte uitgenodigd voor de receptieAnouk Zaalanouk.zaal@gmail.comParanimfenRichard Pouwrbpouw@hotmail.comO6-12136137Lisa Vogelpoellisa.vogelpoel@gmail.com06-44886012    C5aR and TLR Crosstalk                    Anouk Zaal         2018C5aR and TLR Crosstalk:Regulatory effect of anaphylatoxin C5a on human dendritic cellsAnouk ZaalThe research described in this thesis was performed at the department of Immunopathology of Sanquin Research, Amsterdam, The Netherlands. The research was financially supported by Viropharma (unrestricted grant). The printing of this thesis was financially supported by Sanquin Research.Copyright © Anouk Zaal, 2018ISBN:  978-94-6233-864-7Cover design: Anouk ZaalLay-out:  Jasper Koning | koningjj@gmail.comPrinted by GildeprintC5aR and TLR Crosstalk:Regulatory effect of anaphylatoxin C5a on human dendritic cellsACADEMISCH PROEFSCHRIFTTer verkrijging van de graad van doctoraan de Universiteit van Amsterdamop gezag van de Rector Magnificusprof. dr. ir. K.I.J. Maexten overstaan van een door het College van Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapelop donderdag 22 februari 2018, te 10.00 uurdoor Anouk Zaalgeboren te ZaanstadPromotiecommissiePromotor: prof. dr. S. M. van Ham  Universiteit van AmsterdamCopromotor: dr. J. A. ten Brinke  Sanquin ResearchOverige leden: prof. dr. J. Borst  Universiteit van Amsterdam  prof. dr. S. Florquin  Universiteit van Amsterdam  prof. dr. E. C. de Jong  Universiteit van Amsterdam  prof. dr. C. van Kooten  Universiteit Leiden  prof. dr. J. J. Voorberg  Universiteit van Amsterdam  prof. dr. H. V. Westerhoff Universiteit van Amsterdam  dr. ing. S. J. van Vliet  Vrije universiteitFaculteit der Natuurwetenschappen, Wiskunde en InformaticaLPS C5aexpressionC5aR croTLRDCsproductioncomplementinducedmoDimmcell genytokine C5aR1C5aR2ICsTNFD1c17 function MSKvia humansvitroATF3proteincullevelsD14APCpresenceDCsIL10contraststimulibeforeSPHK1SPAmoredataMDC8RSK2�lowTLRsMDC1TFOXOGIPR C5L2CD3synergylocallyMyD88C5aRAGPCRslesspDCsskinS1PVoor mijn mannen,    Giso en Cas LPS C5aexpressionC5aR croTLRDCsproductioncomplementinducedmoDimmcell genytokine C5aR1C5aR2ICsTNFD1c17 function MSKvia humansvitroATF3proteincullevelsD14APCpresenceDCsIL10contraststimulibeforeSPHK1SPAmoredataMDC8RSK2�lowTLRsMDC1TFOXOGIPR C5L2CD3synergylocallyMyD88C5aRAGPCRslesspDCsskinS1PChapter 1 Chapter 2 Chapter 3  Chapter 4 Chapter 5 Chapter 6Chapter 7General introduction and scope of this thesisCrosstalk between Toll-like receptors and C5a receptor in human monocyte-derived DCs suppresses inflammatory cytokine productionAnaphylatoxin C5a regulates 6-Sulfo-LacNAc dendritic cell function in human through crosstalk with Toll-like receptor-induced CREB signalingTLR4 and C5aR crosstalk in dendritic cells induces a core regulatory network of RSK2, PI3Kβ, SGK1, and FOXO transcription factorsThe anaphylatoxin C5a attenuates Fc-gamma receptor-mediated uptake of immune complexes by human dendritic cellsSummarizing discussionAddendumEnglish summaryNederlandse samenvattingList of publicationsList of co-authors and their contribution to the manuscriptPhD PortfolioCurriculum VitaeDankwoord11334777129145167168171175176178180181Table of contents

C5aR and TLR crosstalk:Regulatory effect of anaphylatoxin C5a on human dendritic cells

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C5aR and TLR crosstalk:Regulatory effect of anaphylatoxin C5a on human dendritic cells

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