Innate Immunity and Metabolic Inflammation

Research Focus

The scientific focus of the group is in the field of Innate Immunity and metabolic inflammation. We aim at identifying inflammatory mechanisms that are involved in the regulation of acute as well as of chronic inflammation in the context of metabolic-inflammatory pathologies (type 2 diabetes, Non-Alcoholic Fatty Liver disease), inflammatory bone loss and cancer.

At the molecular level, our group studies:

(a) The molecular mechanisms governing leukocyte recruitment and activation in the course of inflammation as well as the mechanisms involved in resolution of inflammation (Chavakis / Chung).

(b) The regulation of innate immune cell generation (myelopoiesis) in the bone marrow as well as the regulation of the mechanisms underlying trained innate immunity (innate immune memory) (Chavakis).

(c) The mechanisms of the crosstalk between inflammation and metabolism at the cellular and systemic organism level. For instance, we analyze the role inflammation in the adipose tissue and the liver in the context of obesity (Chavakis / Chung).

Specific expertise

Inflammation / Innate Immunity:

Leukocyte adhesion and recruitment
Integrins
Trained Immunity
Hematopoiesis / Myelopoiesis
Tumor Immunology
Bone Inflammation

Metabolic Inflammation

Obesity / Adipose tissue inflammation / Type 2 Diabetes
Non-Alcoholic Fatty Liver Disease (NAFLD)
Cell metabolism

Funding

Lab Members

Prof. Dr. Chavakis, Triantafyllos	Principal Investigator
Dr. Anjanappa, Raghavendra	Postdoc	E-Mail
Dr. Chung, Kyoung-Jin	Senior Staff Scientist / Co-PI	E-Mail
Gebler, Janine	Technician	E-Mail
Dr. Gembardt, Stephanie	Scientific Coordinator	E-Mail
Gercken, Bettina	Technician	E-Mail
Großklaus, Sylvia	Labmanager	E-Mail
Haacke, Nora	MD Student	E-Mail
Ioannidis, Charalampos	Technician	E-Mail
Dr. Kim, Dong-Young	Postdoc	E-Mail
Dr. Nagai, Kosuke	Postdoc	E-Mail
Prucnal, Marta	Technician	E-Mail
Dr. Sharma, Reshma	Postdoc	E-Mail
Dr. Subramanian, Pallavi	Senior Postdoc	E-Mail
Dr. Trimaglio, Giulia	Postdoc	E-Mail
Yan, Shu	PhD Student	E-Mail
Yiannakou, Danae	PhD Student	E-Mail

Selected Publications

Chavakis T, Wielockx B, Hajishengallis G. . Inflammatory Modulation of Hematopoiesis: Linking Trained Immunity and Clonal Hematopoiesis with Chronic Disorders. Annu Rev Physiol.2022 Feb 10;84:183-207.
Subramanian P, Gargani S, Palladini A, Chatzimike M, Grzybek M, Peitzsch M, Papanastasiou AD, Pyrina I, Ntafis V, Gercken B, Lesche M, Petzold P, Sinha A, Nati M, Thangapandi VR, Kourtzelis I, Andreadou M, Witt A, Dahl A, Burkhardt R, Haase R, Domingues AMJ, Henry I, Zamboni N, Mirtschink P, Chung KJ, Hampe J, Coskun Ü, Kontoyiannis DL, Chavakis T. The RNA binding protein human antigen R is a gatekeeper of liver homeostasis. Hepatology Apr;75(4):881-897.
Dudeck J, Kotrba J, Immler R, Hoffmann A, Voss M, Alexaki VA, Morton L, Jahn SR, Katsoulis-Dimitriou K, Winzer S, Kollias G, Fischer T, Nedospasov SA, Dunay IR, Chavakis T, Müller AJ, Schraven B, Sperandio M, Dudeck A. Directional mast cell degranulation of tumor necrosis factor into blood vessels primes neutrophil extravasation. Immunity 2021 Mar 9;54(3):468-483.e5.
Nati M, Chung KJ, Chavakis T. The Role of Innate Immune Cells in Nonalcoholic Fatty Liver Disease. J Innate Immun. 2022;14(1):31-41.
Li X, Wang H, Yu X, Saha G, Kalafati L, Ioannidis C, Mitroulis I, Netea MG, Chavakis T, Hajishengallis G. Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities. Cell. 2022 May 12;185(10):1709-1727.e18.

Peuker K, Strigli A, Tauriello DVF, Hendricks A, von Schönfels W, Burmeister G, Brosch M, Herrmann A, Krüger S, Nitsche N, Južnić L, Geissler MM, Hiergeist A, Gessner A, Wirbel J, Ponnudurai RP, Tunger A, Wehner R, Stange DE, Weitz J, Aust DE, Baretton GB, Schmitz M, Röcken C, Hampe J, Hinz S, Zeller G, Chavakis T, Schafmayer C, Batlle E, Zeissig S. Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer. Immunity. 2022 Apr 12;55(4):701-717.e7.

Wang H, Li X, Kajikawa T, Shin J, Lim HJ, Kourtzelis K, Nagai K, Korostoff JM, Grossklaus S, Naumann R, Chavakis T, Hajishengallis G. Stromal cell-derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis. Stromal cell-derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis- J Clin Invest 131(19)(2021)
Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol 21(7):426-440 (2021)
Alissafi, T, Kalafati, L, Lazari, M, Filia, A, Kloukina, I, Manifava, M, Lim, J H, Alexaki, V I, Ktistakis, N T, Doskas, T, Garinis, G A, Chavakis, T, Boumpas, D T and Verginis, P. Mitochondrial Oxidative Damage Underlies Regulatory T Cell Defects in Autoimmunity. Cell Metab 32: 591-604 e7 (2020)
Hatzioannou, A, Banos, A, Sakelaropoulos, T, Fedonidis, C, Vidali, M S, Kohne, M, Handler, K, Boon, L, Henriques, A, Koliaraki, V, Georgiadis, P, Zoidakis, J, Termentzi, A, Beyer, M, Chavakis, T, Boumpas, D, Tsirigos, A and Verginis, P. An intrinsic role of IL-33 in Treg cell-mediated tumor immunoevasion. Nat Immunol 21: 75-85 (2020)
Kalafati, L, Kourtzelis, I, Schulte-Schrepping, J, Li, X, Hatzioannou, A, Grinenko, T, Hagag, E, Sinha, A, Has, C, Dietz, S, de Jesus Domingues, A M, Nati, M, Sormendi, S, Neuwirth, A, Chatzigeorgiou, A, Ziogas, A, Lesche, M, Dahl, A, Henry, I, Subramanian, P, Wielockx, B, Murray, P, Mirtschink, P, Chung, K J, Schultze, J L, Netea, M G, Hajishengallis, G, Verginis, P, Mitroulis, I and Chavakis, T. Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity. Cell 183: 771-785 e12 (2020)
Li, X, Colamatteo, A, Kalafati, L, Kajikawa, T, Wang, H, Lim, J H, Bdeir, K, Chung, K J, Yu, X, Fusco, C, Porcellini, A, De Simone, S, Matarese, G, Chavakis, T, De Rosa, V and Hajishengallis, G. The DEL-1/beta3 integrin axis promotes regulatory T cell responses during inflammation resolution. J Clin Invest 130: 6261-6277 (2020)
Moorlag, S, Rodriguez-Rosales, Y A, Gillard, J, Fanucchi, S, Theunissen, K, Novakovic, B, de Bont, C M, Negishi, Y, Fok, E T, Kalafati, L, Verginis, P, Mourits, V P, Koeken, V, de Bree, L C J, Pruijn, G J M, Fenwick, C, van Crevel, R, Joosten, L A B, Joosten, I, Koenen, H, Mhlanga, M M, Diavatopoulos, D A, Chavakis, T and Netea, M G. BCG Vaccination Induces Long-Term Functional Reprogramming of Human Neutrophils. Cell Rep 33: 108387 (2020)
Chavakis, T, Mitroulis, I and Hajishengallis, G. Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation. Nat Immunol 20: 802-811 (2019)
Kourtzelis, I, Li, X, Mitroulis, I, Grosser, D, Kajikawa, T, Wang, B, Grzybek, M, von Renesse, J, Czogalla, A, Troullinaki, M, Ferreira, A, Doreth, C, Ruppova, K, Chen, L S, Hosur, K, Lim, J H, Chung, K J, Grossklaus, S, Tausche, A K, Joosten, L A B, Moutsopoulos, N M, Wielockx, B, Castrillo, A, Korostoff, J M, Coskun, U, Hajishengallis, G and Chavakis, T. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat Immunol 20: 40-49 (2019)
Wang, B, Lim, J H, Kajikawa, T, Li, X, Vallance, B A, Moutsopoulos, N M, Chavakis, T and Hajishengallis, G. Macrophage beta2-Integrins Regulate IL-22 by ILC3s and Protect from Lethal Citrobacter rodentium-Induced Colitis. Cell Rep 26: 1614-1626 e5 (2019)
Mitroulis, I, Ruppova, K, Wang, B, Chen, L S, Grzybek, M, Grinenko, T, Eugster, A, Troullinaki, M, Palladini, A, Kourtzelis, I, Chatzigeorgiou, A, Schlitzer, A, Beyer, M, Joosten, L A B, Isermann, B, Lesche, M, Petzold, A, Simons, K, Henry, I, Dahl, A, Schultze, J L, Wielockx, B, Zamboni, N, Mirtschink, P, Coskun, U, Hajishengallis, G, Netea, M G and Chavakis, T. Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity. Cell 172: 147-161 e12 (2018)
Chung, K J, Chatzigeorgiou, A, Economopoulou, M, Garcia-Martin, R, Alexaki, V I, Mitroulis, I, Nati, M, Gebler, J, Ziemssen, T, Goelz, S E, Phieler, J, Lim, J H, Karalis, K P, Papayannopoulou, T, Bluher, M, Hajishengallis, G and Chavakis, T. A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat Immunol 18: 654-664 (2017)
Mitroulis, I, Chen, L S, Singh, R P, Kourtzelis, I, Economopoulou, M, Kajikawa, T, Troullinaki, M, Ziogas, A, Ruppova, K, Hosur, K, Maekawa, T, Wang, B, Subramanian, P, Tonn, T, Verginis, P, von Bonin, M, Wobus, M, Bornhauser, M, Grinenko, T, Di Scala, M, Hidalgo, A, Wielockx, B, Hajishengallis, G and Chavakis, T. Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche. J Clin Invest 127: 3624-3639 (2017)
Choi, E Y, Lim, J H, Neuwirth, A, Economopoulou, M, Chatzigeorgiou, A, Chung, K J, Bittner, S, Lee, S H, Langer, H, Samus, M, Kim, H, Cho, G S, Ziemssen, T, Bdeir, K, Chavakis, E, Koh, J Y, Boon, L, Hosur, K, Bornstein, S R, Meuth, S G, Hajishengallis, G and Chavakis, T. Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol Psychiatry 20: 880-888 (2015)
Maekawa, T, Hosur, K, Abe, T, Kantarci, A, Ziogas, A, Wang, B, Van Dyke, T E, Chavakis, T and Hajishengallis, G. Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3beta-C/EBPbeta pathway. Nat Commun 6: 8272 (2015)
Pruenster, M, Kurz, A R, Chung, K J, Cao-Ehlker, X, Bieber, S, Nussbaum, C F, Bierschenk, S, Eggersmann, T K, Rohwedder, I, Heinig, K, Immler, R, Moser, M, Koedel, U, Gran, S, McEver, R P, Vestweber, D, Verschoor, A, Leanderson, T, Chavakis, T, Roth, J, Vogl, T and Sperandio, M. Extracellular MRP8/14 is a regulator of beta2 integrin-dependent neutrophil slow rolling and adhesion. Nat Commun 6: 6915 (2015)
Shin, J, Maekawa, T, Abe, T, Hajishengallis, E, Hosur, K, Pyaram, K, Mitroulis, I, Chavakis, T and Hajishengallis, G. DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates. Sci Transl Med 7: 307ra155 (2015)
Weber, G F, Chousterman, B G, He, S, Fenn, A M, Nairz, M, Anzai, A, Brenner, T, Uhle, F, Iwamoto, Y, Robbins, C S, Noiret, L, Maier, S L, Zonnchen, T, Rahbari, N N, Scholch, S, Klotzsche-von Ameln, A, Chavakis, T, Weitz, J, Hofer, S, Weigand, M A, Nahrendorf, M, Weissleder, R and Swirski, F K. Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 347: 1260-5 (2015)
Chatzigeorgiou, A, Chung, K J, Garcia-Martin, R, Alexaki, V I, Klotzsche-von Ameln, A, Phieler, J, Sprott, D, Kanczkowski, W, Tzanavari, T, Bdeir, M, Bergmann, S, Cartellieri, M, Bachmann, M, Nikolakopoulou, P, Androutsellis-Theotokis, A, Siegert, G, Bornstein, S R, Muders, M H, Boon, L, Karalis, K P, Lutgens, E and Chavakis, T. Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology 60: 1196-210 (2014)
Chatzigeorgiou, A, Seijkens, T, Zarzycka, B, Engel, D, Poggi, M, van den Berg, S, van den Berg, S, Soehnlein, O, Winkels, H, Beckers, L, Lievens, D, Driessen, A, Kusters, P, Biessen, E, Garcia-Martin, R, Klotzsche-von Ameln, A, Gijbels, M, Noelle, R, Boon, L, Hackeng, T, Schulte, K M, Xu, A, Vriend, G, Nabuurs, S, Chung, K J, Willems van Dijk, K, Rensen, P C, Gerdes, N, de Winther, M, Block, N L, Schally, A V, Weber, C, Bornstein, S R, Nicolaes, G, Chavakis, T and Lutgens, E. Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proc Natl Acad Sci U S A 111: 2686-91 (2014)
Phieler, J, Chung, K J, Chatzigeorgiou, A, Klotzsche-von Ameln, A, Garcia-Martin, R, Sprott, D, Moisidou, M, Tzanavari, T, Ludwig, B, Baraban, E, Ehrhart-Bornstein, M, Bornstein, S R, Mziaut, H, Solimena, M, Karalis, K P, Economopoulou, M, Lambris, J D and Chavakis, T. The complement anaphylatoxin C5a receptor contributes to obese adipose tissue inflammation and insulin resistance. J Immunol 191: 4367-74 (2013)
Eskan, M A, Jotwani, R, Abe, T, Chmelar, J, Lim, J H, Liang, S, Ciero, P A, Krauss, J L, Li, F, Rauner, M, Hofbauer, L C, Choi, E Y, Chung, K J, Hashim, A, Curtis, M A, Chavakis, T and Hajishengallis, G. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol 13: 465-73 (2012)
Langer, H F, Choi, E Y, Zhou, H, Schleicher, R, Chung, K J, Tang, Z, Gobel, K, Bdeir, K, Chatzigeorgiou, A, Wong, C, Bhatia, S, Kruhlak, M J, Rose, J W, Burns, J B, Hill, K E, Qu, H, Zhang, Y, Lehrmann, E, Becker, K G, Wang, Y, Simon, D I, Nieswandt, B, Lambris, J D, Li, X, Meuth, S G, Kubes, P and Chavakis, T. Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis. Circ Res 110: 1202-10 (2012)
Langer, H F, Orlova, V V, Xie, C, Kaul, S, Schneider, D, Lonsdorf, A S, Fahrleitner, M, Choi, E Y, Dutoit, V, Pellegrini, M, Grossklaus, S, Nawroth, P P, Baretton, G, Santoso, S, Hwang, S T, Arnold, B and Chavakis, T. A novel function of junctional adhesion molecule-C in mediating melanoma cell metastasis. Cancer Res 71: 4096-105 (2011)
Langer, H F, Chung, K J, Orlova, V V, Choi, E Y, Kaul, S, Kruhlak, M J, Alatsatianos, M, DeAngelis, R A, Roche, P A, Magotti, P, Li, X, Economopoulou, M, Rafail, S, Lambris, J D and Chavakis, T. Complement-mediated inhibition of neovascularization reveals a point of convergence between innate immunity and angiogenesis. Blood 116: 4395-403 (2010)
Economopoulou, M, Langer, H F, Celeste, A, Orlova, V V, Choi, E Y, Ma, M, Vassilopoulos, A, Callen, E, Deng, C, Bassing, C H, Boehm, M, Nussenzweig, A and Chavakis, T. Histone H2AX is integral to hypoxia-driven neovascularization. Nat Med 15: 553-8 (2009)
Choi, E Y, Chavakis, E, Czabanka, M A, Langer, H F, Fraemohs, L, Economopoulou, M, Kundu, R K, Orlandi, A, Zheng, Y Y, Prieto, D A, Ballantyne, C M, Constant, S L, Aird, W C, Papayannopoulou, T, Gahmberg, C G, Udey, M C, Vajkoczy, P, Quertermous, T, Dimmeler, S, Weber, C and Chavakis, T. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 322: 1101-4 (2008)
Choi, E Y, Orlova, V V, Fagerholm, S C, Nurmi, S M, Zhang, L, Ballantyne, C M, Gahmberg, C G and Chavakis, T. Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins. Blood 111: 3607-14 (2008)
Orlova, V V, Choi, E Y, Xie, C, Chavakis, E, Bierhaus, A, Ihanus, E, Ballantyne, C M, Gahmberg, C G, Bianchi, M E, Nawroth, P P and Chavakis, T. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J 26: 1129-39 (2007)
Orlova, V V, Economopoulou, M, Lupu, F, Santoso, S and Chavakis, T. Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin-mediated cell-cell contacts. J Exp Med 203: 2703-14 (2006)