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JOURNAL ARTICLE
G Hajishengallis, T Chavakis
Neutrophils are abundant, short-lived myeloid cells that are readily recruitable to sites of inflammation, where they serve as first-line defense against infection and other types of insult to the host. In recent years, there has been increased understanding on the involvement of neutrophils in chronic inflammatory diseases, where they may act as direct effectors of destructive inflammation. However, destructive tissue inflammation is also instigated in settings of neutrophil paucity, suggesting that neutrophils also mediate critical homeostatic functions...
July 4, 2022: Journal of Dental Research
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JOURNAL ARTICLE
Mathias Langner, Ivona Mateska, Nicole Bechmann, Ben Wielockx, Triantafyllos Chavakis, Vasileia Ismini Alexaki, Mirko Peitzsch
The conditionally essential amino acid arginine and its metabolic products play an important role in different biological processes, such as metabolic regulation of the immune response, including macrophage activation and polarization and regulation of T cell function. Furthermore, the polyamine spermidine has a role in aging and age-related diseases. Additionally, altered polyamine metabolism may be associated with neurodegenerative diseases, while polyamine levels may present useful biomarkers associated with severity of Parkinson's disease or with progression of non-alcoholic fatty liver disease...
May 24, 2022: Journal of Chromatography. A
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JOURNAL ARTICLE
Kenneth Peuker, Anne Strigli, Daniele V F Tauriello, Alexander Hendricks, Witigo von Schönfels, Greta Burmeister, Mario Brosch, Alexander Herrmann, Sandra Krüger, Jessica Nitsche, Lea Južnić, Marc Marius Geissler, Andreas Hiergeist, André Gessner, Jakob Wirbel, Ruby Priyadarshini Ponnudurai, Antje Tunger, Rebekka Wehner, Daniel E Stange, Jürgen Weitz, Daniela E Aust, Gustavo B Baretton, Marc Schmitz, Christoph Röcken, Jochen Hampe, Sebastian Hinz, Georg Zeller, Triantafyllos Chavakis, Clemens Schafmayer, Eduard Batlle, Sebastian Zeissig
Bacterial sensing by intestinal tumor cells contributes to tumor growth through cell-intrinsic activation of the calcineurin-NFAT axis, but the role of this pathway in other intestinal cells remains unclear. Here, we found that myeloid-specific deletion of calcineurin in mice activated protective CD8+ T cell responses and inhibited colorectal cancer (CRC) growth. Microbial sensing by myeloid cells promoted calcineurin- and NFAT-dependent interleukin 6 (IL-6) release, expression of the co-inhibitory molecules B7H3 and B7H4 by tumor cells, and inhibition of CD8+ T cell-dependent anti-tumor immunity...
April 12, 2022: Immunity
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JOURNAL ARTICLE
Anne von Mässenhausen, Nadia Zamora Gonzalez, Francesca Maremonti, Alexia Belavgeni, Wulf Tonnus, Claudia Meyer, Kristina Beer, Monica T Hannani, Arthur Lau, Mirko Peitzsch, Paul Hoppenz, Sophie Locke, Triantafyllos Chavakis, Rafael Kramann, Daniel A Muruve, Christian Hugo, Stefan R Bornstein, Andreas Linkermann
Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner...
February 4, 2022: Science Advances
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JOURNAL ARTICLE
Elisa Jentho, Cristian Ruiz-Moreno, Boris Novakovic, Ioannis Kourtzelis, Wout L Megchelenbrink, Rui Martins, Triantafyllos Chavakis, Miguel P Soares, Lydia Kalafati, Joel Guerra, Franziska Roestel, Peter Bohm, Maren Godmann, Tatyana Grinenko, Anne Eugster, Martina Beretta, Leo A B Joosten, Mihai G Netea, Michael Bauer, Hendrik G Stunnenberg, Sebastian Weis
Trained immunity defines long-lasting adaptations of innate immunity based on transcriptional and epigenetic modifications of myeloid cells and their bone marrow progenitors [M. Divangahi et al., Nat. Immunol. 22, 2-6 (2021)]. Innate immune cells, however, do not exclusively differentiate between foreign and self but also react to host-derived molecules referred to as alarmins. Extracellular "labile" heme, released during infections, is a bona fide alarmin promoting myeloid cell activation [M. P. Soares, M...
October 19, 2021: Proceedings of the National Academy of Sciences of the United States of America
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JOURNAL ARTICLE
Hui Wang, Xiaofei Li, Tetsuhiro Kajikawa, Jieun Shin, Jong-Hyung Lim, Ioannis Kourtzelis, Kosuke Nagai, Jonathan Korostoff, Sylvia Grossklaus, Ronald Naumann, Triantafyllos Chavakis, George Hajishengallis
The secreted protein DEL-1 regulates inflammatory cell recruitment and protects against inflammatory pathologies in animal models. Here, we investigated DEL-1 in inflammatory arthritis using collagen-induced arthritis (CIA) and collagen Ab-induced arthritis (CAIA). In both models, mice with endothelial-specific overexpression of DEL-1 were protected from arthritis relative to WT controls, while arthritis was exacerbated in DEL-1-deficient mice. Compared to WT controls, mice with collagen VI promoter-driven overexpression of DEL-1 in mesenchymal cells were protected against CIA but not CAIA, suggesting a role for DEL-1 in the induction of the arthritogenic Ab response...
August 17, 2021: Journal of Clinical Investigation
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REVIEW
Malte von Bonin, Helena Klara Jambor, Raphael Teipel, Friedrich Stölzel, Christian Thiede, Frederik Damm, Frank Kroschinsky, Johannes Schetelig, Triantafyllos Chavakis, Martin Bornhäuser
The accumulation of somatic mutations in hematopoietic stem cells during aging, leading to clonal expansion, is linked to a higher risk of cardiovascular mortality and hematologic malignancies. Clinically, clonal hematopoiesis is associated with a pro-inflammatory phenotype of hematopoietic cells and their progeny, inflammatory conditions and a poor outcome for patients with hematologic neoplasms and solid tumors. Here, we review the relevance and complications of clonal hematopoiesis for the treatment of hematologic malignancies with cell therapeutic approaches...
October 2021: Leukemia
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JOURNAL ARTICLE
S R Bornstein, K Guan, C Brunßen, G Mueller, V Kamvissi-Lorenz, R Lechler, R Trembath, M Mayr, L Poston, R Sancho, S Ahmed, E Alfar, B Aljani, T C Alves, S Amiel, C L Andoniadou, M Bandral, A Belavgeni, I Berger, A Birkenfeld, E Bonifacio, T Chavakis, P Chawla, P Choudhary, A M Cujba, L F Delgadillo Silva, T Demcollari, D M Drotar, S Duin, N N El-Agroudy, A El-Armouche, A Eugster, M Gado, A Gavalas, M Gelinsky, M Guirgus, S Hansen, E Hanton, M Hasse, H Henneicke, C Heller, H Hempel, C Hogstrand, D Hopkins, L Jarc, P M Jones, M Kamel, S Kämmerer, A J F King, A Kurzbach, C Lambert, Y Latunde-Dada, I Lieberam, J Liers, J W Li, A Linkermann, S Locke, B Ludwig, T Manea, F Maremonti, Z Marinicova, B M McGowan, M Mickunas, G Mingrone, K Mohanraj, H Morawietz, N Ninov, M Peakman, S J Persaud, J Pietzsch, E Cachorro, T J Pullen, I Pyrina, F Rubino, A Santambrogio, F Schepp, P Schlinkert, L D Scriba, R Siow, M Solimena, F M Spagnoli, S Speier, A Stavridou, C Steenblock, A Strano, P Taylor, A Tiepner, W Tonnus, T Tree, F Watt, M Werdermann, M Wilson, N Yusuf, C G Ziegler
Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society...
March 2021: Hormone and Metabolic Research
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JOURNAL ARTICLE
Simone J C F M Moorlag, Yessica Alina Rodriguez-Rosales, Joshua Gillard, Stephanie Fanucchi, Kate Theunissen, Boris Novakovic, Cynthia M de Bont, Yutaka Negishi, Ezio T Fok, Lydia Kalafati, Panayotis Verginis, Vera P Mourits, Valerie A C M Koeken, L Charlotte J de Bree, Ger J M Pruijn, Craig Fenwick, Reinout van Crevel, Leo A B Joosten, Irma Joosten, Hans Koenen, Musa M Mhlanga, Dimitri A Diavatopoulos, Triantafyllos Chavakis, Mihai G Netea
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) protects against some heterologous infections, probably via induction of non-specific innate immune memory in monocytes and natural killer (NK) cells, a process known as trained immunity. Recent studies have revealed that the induction of trained immunity is associated with a bias toward granulopoiesis in bone marrow hematopoietic progenitor cells, but it is unknown whether BCG vaccination also leads to functional reprogramming of mature neutrophils. Here, we show that BCG vaccination of healthy humans induces long-lasting changes in neutrophil phenotype, characterized by increased expression of activation markers and antimicrobial function...
November 17, 2020: Cell Reports
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JOURNAL ARTICLE
Donato Santovito, Virginia Egea, Kiril Bidzhekov, Lucia Natarelli, André Mourão, Xavier Blanchet, Kanin Wichapong, Maria Aslani, Coy Brunßen, Michael Horckmans, Michael Hristov, Arie Geerlof, Esther Lutgens, Mat J A P Daemen, Tilman Hackeng, Christian Ries, Triantafyllos Chavakis, Henning Morawietz, Ronald Naumann, Philipp Von Hundelshausen, Sabine Steffens, Johan Duchêne, Remco T A Megens, Michael Sattler, Christian Weber
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression which act by guiding AGO (argonaute) proteins to target RNA transcripts in the RNA-induced silencing complex (RISC). This macromolecular complex includes multiple additional components ( e.g ., TNRC6A) that allow for interaction with enzymes mediating inhibition of translation or RNA decay. However, miRNAs also reside in low-molecular weight complexes without being engaged in target repression, and their function in this context is largely unknown...
October 15, 2020: Autophagy
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JOURNAL ARTICLE
Xiaofei Li, Alessandra Colamatteo, Lydia Kalafati, Tetsuhiro Kajikawa, Hui Wang, Jong-Hyung Lim, Khalil Bdeir, Kyoung-Jin Chung, Xiang Yu, Clorinda Fusco, Antonio Porcellini, Salvatore De Simone, Giuseppe Matarese, Triantafyllos Chavakis, Veronica De Rosa, George Hajishengallis
FOXP3+CD4+ regulatory T cells (Tregs) are critical for immune homeostasis and respond to local tissue cues, which control their stability and function. We explored here whether DEL-1, which, like Tregs, increases during resolution of inflammation, promotes Treg responses. DEL-1 enhanced Treg numbers and function at barrier sites (oral and lung mucosa). The underlying mechanism was dissected using mice lacking DEL-1 or expressing a point mutant thereof, or mice with T cell-specific deletion of the transcription factor RUNX1, identified by RNA-seq analysis of the DEL-1-induced Treg transcriptome...
August 20, 2020: Journal of Clinical Investigation
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JOURNAL ARTICLE
Kosuke Nagai, Hidetaka Ideguchi, Tetsuhiro Kajikawa, Xiaofei Li, Triantafyllos Chavakis, Jing Cheng, Phillip B Messersmith, Ellen Heber-Katz, George Hajishengallis
The hypoxia-inducible factor 1α (HIF-1α) is critically involved in tissue regeneration. Hence, the pharmacological prevention of HIF-1α degradation by prolyl hydroxylase (PHD) under normoxic conditions is emerging as a promising option in regenerative medicine. Using a mouse model of ligature-induced periodontitis and resolution, we tested the ability of an injectable hydrogel-formulated PHD inhibitor, 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA/hydrogel), to promote regeneration of alveolar bone lost owing to experimental periodontitis...
October 2020: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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JOURNAL ARTICLE
Themis Alissafi, Lydia Kalafati, Maria Lazari, Anastasia Filia, Ismini Kloukina, Maria Manifava, Jong-Hyung Lim, Vasileia Ismini Alexaki, Nicholas T Ktistakis, Triantafyllos Doskas, George A Garinis, Triantafyllos Chavakis, Dimitrios T Boumpas, Panayotis Verginis
Regulatory T cells (Tregs) are vital for the maintenance of immune homeostasis, while their dysfunction constitutes a cardinal feature of autoimmunity. Under steady-state conditions, mitochondrial metabolism is critical for Treg function; however, the metabolic adaptations of Tregs during autoimmunity are ill-defined. Herein, we report that elevated mitochondrial oxidative stress and a robust DNA damage response (DDR) associated with cell death occur in Tregs in individuals with autoimmunity. In an experimental autoimmune encephalitis (EAE) mouse model of autoimmunity, we found a Treg dysfunction recapitulating the features of autoimmune Tregs with a prominent mtROS signature...
October 6, 2020: Cell Metabolism
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MULTICENTER STUDY
Veera Raghavan Thangapandi, Oskar Knittelfelder, Mario Brosch, Eleonora Patsenker, Olga Vvedenskaya, Stephan Buch, Sebastian Hinz, Alexander Hendricks, Marina Nati, Alexander Herrmann, Devavrat Ravindra Rekhade, Thomas Berg, Madlen Matz-Soja, Klaus Huse, Edda Klipp, Josch K Pauling, Judith Ah Wodke, Jacobo Miranda Ackerman, Malte von Bonin, Elmar Aigner, Christian Datz, Witigo von Schönfels, Sophie Nehring, Sebastian Zeissig, Christoph Röcken, Andreas Dahl, Triantafyllos Chavakis, Felix Stickel, Andrej Shevchenko, Clemens Schafmayer, Jochen Hampe, Pallavi Subramanian
OBJECTIVE: The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. DESIGN: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep ) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics...
May 2021: Gut
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JOURNAL ARTICLE
Donato Santovito, Virginia Egea, Kiril Bidzhekov, Lucia Natarelli, André Mourão, Xavier Blanchet, Kanin Wichapong, Maria Aslani, Coy Brunßen, Michael Horckmans, Michael Hristov, Arie Geerlof, Esther Lutgens, Mat J A P Daemen, Tilman Hackeng, Christian Ries, Triantafyllos Chavakis, Henning Morawietz, Ronald Naumann, Philipp von Hundelshausen, Sabine Steffens, Johan Duchêne, Remco T A Megens, Michael Sattler, Christian Weber
MicroRNAs (miRNAs) are versatile regulators of gene expression with profound implications for human disease including atherosclerosis, but whether they can exert posttranslational functions to control cell adaptation and whether such noncanonical features harbor pathophysiological relevance is unknown. Here, we show that miR-126-5p sustains endothelial integrity in the context of high shear stress and autophagy. Bound to argonaute-2 (Ago2), miR-126-5p forms a complex with Mex3a, which occurs on the surface of autophagic vesicles and guides its transport into the nucleus...
June 3, 2020: Science Translational Medicine
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JOURNAL ARTICLE
Aikaterini Hatzioannou, Aggelos Banos, Theodore Sakelaropoulos, Constantinos Fedonidis, Maria-Sophia Vidali, Maren Köhne, Kristian Händler, Louis Boon, Ana Henriques, Vasiliki Koliaraki, Panagiotis Georgiadis, Jerome Zoidakis, Aikaterini Termentzi, Marc Beyer, Triantafyllos Chavakis, Dimitrios Boumpas, Aristotelis Tsirigos, Panayotis Verginis
Regulatory T (Treg ) cells accumulate into tumors, hindering the success of cancer immunotherapy. Yet, therapeutic targeting of Treg cells shows limited efficacy or leads to autoimmunity. The molecular mechanisms that guide Treg cell stability in tumors remain elusive. In the present study, we identify a cell-intrinsic role of the alarmin interleukin (IL)-33 in the functional stability of Treg cells. Specifically, IL-33-deficient Treg cells demonstrated attenuated suppressive properties in vivo and facilitated tumor regression in a suppression of tumorigenicity 2 receptor (ST2) (IL-33 receptor)-independent fashion...
January 2020: Nature Immunology
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JOURNAL ARTICLE
Andreea-Manuela Mirea, Erik J M Toonen, Inge van den Munckhof, Isabelle D Munsterman, Eric T T L Tjwa, Martin Jaeger, Marije Oosting, Kiki Schraa, Joost H W Rutten, Marinette van der Graaf, Niels P Riksen, Jacqueline de Graaf, Mihai G Netea, Cees J Tack, Triantafyllos Chavakis, Leo A B Joosten
INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). The aim of this study was to investigate whether PR3 and NE plasma concentrations are associated with NAFLD and/or type 2 diabetes...
May 2, 2019: Molecular Medicine
#18
REVIEW
Antigoni Poultsidi, Yiannis Dimopoulos, Ting-Fang He, Triantafyllos Chavakis, Emmanouil Saloustros, Peter P Lee, Constantinos Petrovas
Lymph nodes (LNs) are central in the generation of adaptive immune responses. Follicular helper CD4 T (Tfh) cells, a highly differentiated CD4 population, provide critical help for the development of antigen-specific B cell responses within the germinal center. Throughout the past decade, numerous studies have revealed the important role of Tfh cells in Human Immunodeficiency Virus (HIV) pathogenesis as well as in the development of neutralizing antibodies post-infection and post-vaccination. It has also been established that tumors influence various immune cell subsets not only in their proximity, but also in draining lymph nodes...
2018: Frontiers in Immunology
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JOURNAL ARTICLE
Irina Korovina, Ales Neuwirth, David Sprott, Silvio Weber, Sheik Pran Babu Sardar Pasha, Bettina Gercken, Georg Breier, Ali El-Armouche, Andreas Deussen, Mike O Karl, Ben Wielockx, Triantafyllos Chavakis, Anne Klotzsche-von Ameln
A hallmark of proliferative retinopathies, such as retinopathy of prematurity (ROP), is a pathological neovascularization orchestrated by hypoxia and the resulting hypoxia-inducible factor (HIF)-dependent response. We studied the role of Hif2α in hematopoietic cells for pathological retina neovascularization in the murine model of ROP, the oxygen-induced retinopathy (OIR) model. Hematopoietic-specific deficiency of Hif2α ameliorated pathological neovascularization in the OIR model, which was accompanied by enhanced endothelial cell apoptosis...
August 29, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
#20
JOURNAL ARTICLE
Maria Moysidou, Sevasti Karaliota, Elisavet Kodela, Maria Salagianni, Yassemi Koutmani, Antonia Katsouda, Konstantia Kodella, Panagiotis Tsakanikas, Styliani Ourailidou, Evangelos Andreakos, Nikolaos Kostomitsopoulos, Dimitris Skokos, Antonios Chatzigeorgiou, Kyoung-Jin Chung, Stefan Bornstein, Mark W Sleeman, Triantafyllos Chavakis, Katia P Karalis
Although accumulation of lymphocytes in the white adipose tissue (WAT) in obesity is linked to insulin resistance, it remains unclear whether lymphocytes also participate in the regulation of energy homeostasis in the WAT. Here, we demonstrate enhanced energy dissipation in Rag1-/- mice, increased catecholaminergic input to subcutaneous WAT, and significant beige adipogenesis. Adoptive transfer experiments demonstrated that CD8+ T cell deficiency accounts for the enhanced beige adipogenesis in Rag1-/- mice...
March 8, 2018: JCI Insight
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