1 p. Annual Scientific Meeting of the European Society for Clinical Investigation Cluj-Napoca, Romania 27– 30 May 2015Peer reviewe

Casas-Engel, Mateo de las

Corbí, Angel L.

Domínguez-Soto, Ángeles

European Journal of Clinical Investigation

Digital.CSIC

5.24Immunoglobulins and Serotonin modulatehuman macrophage polarizationA.L. Corbı´, M. De las Casas-Engel & A. Domınguez-SotoMyeloid Cell Laboratory, Centro de InvestigacionesBiologicas (CIB), Consejo Superior de InvestigacionesCientıficas (CSIC), Madrid, SpainBackground: Macrophages exhibit a huge functional plasticityand can acquire a continuum of polarization states in responseto endogenous and nonself stimuli. Microbe-derived factors, orcytokines like GM-CSF, promote the acquisition of pro-inflam-matory, bactericidal, tumor-suppressive, and immunogenicactivities, a process commonly referred to as M1 polarizationand whose hallmark is the ability to release large amounts ofIL-12/IL-23. Conversely, cytokines like M-CSF promote anti-inflammatory, scavenging, tumor-promoting, tissue repair, andproangiogenic functions (M2 polarization), and the ability toproduce high levels of IL-10. The modulation of macrophagepolarization represents a potential strategy for therapy ofchronic inflammatory pathologies and diseases with an alteredinflammatory status (cancer).Materials and methods: Gene expression profiling was used toidentify genes exclusively expressed in pro-inflammatory oranti-inflammatory human macrophages, and whose validitywas beeen demonstrated through the analysis of macrophagesfrom the sinovial fluid of rheumatoid arthritis patients andtumor-associated macrophages. These biomarkers has been usedto search for factors with ability to promote a shift between themacrophage polarization state.Results: Serotonin inhibits LPS-induced release of proinflam-matory cytokines, upregulates M2 polarization–associated genesand reduces M1-associated genes through through the 5HT7 and5HT2B serotonin receptors. Intravenous immunoglobulinsinduces a M2-to-M1 polarization switch on human and murineM2 macrophages, and limits tumor progression with a concom-itant change in the polarization of tumor-associated myeloidcells via Fc receptors.Conclusions: Serotonin skews macrophage polarizationtowards M2 at the functional and transcriptomic levels, and con-tributes to the maintenance of an anti-inflammatory state via5HT2B and 5HT7. By contrast, Intravenous immunoglobulinspromotes a M2-to-M1 macrophage polarization switch thatmight be therapeutically useful in cancer, in which proinflam-matory or immunogenic functions should be promoted.5.25CARD9 mediates autoantibody-inducedautoimmune diseases by linking the syktyrosine kinase to chemokine productionT. Ne´meth*, K. Futosi*, K. Csorba†, C. Sitaru†, J. Ruland‡ &A. Mocsai**Department of Physiology, Semmelweis University Schoolof Medicine, Budapest, Hungary and MTA-SE ‘Lend€ulet’Inflammation Physiology Research Group of the HungarianAcademy of Sciences and the Semmelweis University;†Department of Dermatology, University Medical Center,Freiburg, Germany; ‡Institut f€ur Klinische Chemie undPathobiochemie, Klinikum rechts der Isar, TechnischeUniversit€at M€unchen, M€unchen, GermanyBackground: In contrast to the well-defined role of CARD9 infungal recognition pathways, its function in non-infectious auto-immune inflammation has not been described yet, despite thefact that a genome-wide association screen raised a possibleassociation between CARD9 gene polymorphisms and a humanautoimmune arthritis. Here, we investigated the role of CARD9in autoantibody-mediated diseases by a transgenic method.Materials and methods: We used the neutrophil-, macrophage-,Fc receptor- and Syk-mediated K/BxN serum transfer arthritisand the anti-collagen type VII antibody-mediated epidermolysisbullosa acquisita (EBA) models. Neutrophils (or macrophages)were stimulated through their Fcc receptors, followed by theanalysis of the superoxide release (as a short-term response) andthe chemokine release (as a long-term response).Results: The absence of CARD9 resulted in a partial, but signif-icant decrease in arthritis severity and CARD9/ mice showeda moderate skin inflammation in the EBA model compared tothe wild type animals. Neutrophil (and monocyte) accumulationat the site of inflammation was strongly reduced in the absenceof CARD9, while CARD9/ neutrophils (and monocytes) hadnormal migratory capacities to the joints in wild type/CARD9/ mixed bone marrow chimeras. Surprisingly, thesynovial levels of the chemokines CXCL1 and CXCL2 were dra-matically reduced in the absence of CARD9 upon arthritisinduction. While Fcc receptor-activated Syk/ neutrophils(and macrophages) failed to produce superoxide or releasechemokines compared to wild type cells among in vitro condi-tions, CARD9/ neutrophils (and macrophages) showed nor-mal short-term, but strongly reduced long-term responses.Conclusions: CARD9 plays an important role in the develop-ment and progression of autoimmune arthritis and autoimmuneblistering skin disease in mice, likely by linking the Syk tyrosinekinase to chemokine production in innate immune cells.T. Nemeth is a recipient of Bolyai Research Fellowship fromthe Hungarian Academy of Sciences.5.26The role of neutrophil extracellular traps in thepathogenesis of obesityQ. Braster*, H. Hartwig*, C. Silvestre-Roig*, E. Lutgens* &O. Soehnlein*†*Department of Pathology, Academic Medical Center (AMC),Amsterdam, the Netherlands; †Institute for CardiovascularPrevention (IPEK), LMU Munich, GermanyBackground: Obesity is a chronic inflammatory disease associ-ated with a prominent mortality and morbidity in western coun-tries. Low-grade chronic inflammation of the adipose tissueresults in insulin resistance and increased cardiovascular risk.During obesity, neutrophils infiltrate the adipose tissue andmediate insulin resistance via the granule-proteins NeutrophilElastase (NE) and myeloperoxidase (MPO). Neutrophils canmake these granule-proteins available extracellularly viadegranulation or via display on Neutrophil Extracellular Traps(NETs). During NET release neutrophils release DNA-proteinstructures as a mechanism of extracellular pathogen killing.However, NET release has also been implied in various patho-logical scenarios including acute lung injury and atherosclerosis.One critical step for NET formation is the chromatin deconden-sation which is associated with histone citrullination, a processcatalyzed by the enzyme PeptidylArginine Deiminase 4(PAD4). Hence, by using the PAD4 inhibitor Cl-amidine, weanalyzed the role of NET release on obesity-mediated pathogen-esis.Material and methods: C57BL/6 mice received a 60% high fatdiet (HFD) for 10 weeks and were injected subcutaneously witha daily dose of 10 mg mL1 kg1 Cl-amidine or vehicle. Todetermine the effect of the HFD a glucose and insulin tolerance© 2015 The Authors. European Journal of Clinical Investigation © 2015 Stichting European Society for Clinical Investigation Journal FoundationEuropean Journal of Clinical Investigation, 45 (Suppl. 2), 4–6854 Workshop 5: Phagocyte Biology

Immunoglobulins and Serotonin modulate human macrophage polarization

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