Professor of Cardiovascular Immunology
Head, Centre for Biochemical Pharmacology
Heart Centre William Harvey Research Institute
Barts and The London SMD
London EC1M 6BQ – UK
The main focus of FMB lab is to investigate the mechanisms that regulate memory and regulatory T cell homing to antigen-rich sites.
We were the first to describe that effector T cell recruitment to antigen-rich parenchymal tissue (including heart allografts) is driven by recognition of antigen on the endothelium1, 2. We have further defined specific molecular mediators of this effect (PI3K p110delta, Vav1), which have been validated in experimental models of disease, and can be pharmacologically targeted to effectively prevent chronic rejection of heart allograft3-5.
Further, we have recently shown that cognate recognition of self-antigen displayed by the endothelium is the dominant mechanism, which sustain regulatory T cell trafficking 6. These studies shed light on the well-known relative inefficiency of the use of autologous Treg in transplantation (non-self endothelium) compared to autoimmunity and will impact on the design of Treg-based adoptive immunotherapies in both these conditions.
In addition, we have reported that the delivery of qualitatively different co-stimulatory signals is key to the dynamic development and ultimately the outcome of an immune response. Specifically, we have shown that positive costimulation via CD28 promotes T cell egress from lymph nodes and localization to antigen-rich non-lymphoid tissue following priming7. In contrast, triggering of the negative co-stimulator CD152 prohibits both these events. These findings bear important relevance in therapeutic settings involving the manipulation of co-stimulatory activity in clinical settings.
Related to this work, we have recently established the impact of interactions mediated by PECAM-1/CD31 on T cell inflammation. The immunoglobulin-like receptor CD31 is expressed by endothelial cells and all leukocytes, including T, B and dendritic cells, and is homophilically engaged on T cells during antigen-presentation by DCs and migration through the endothelium. Our recent studies have revealed a key role for this molecule as a negative co-stimulator in the regulation of T cell homeostasis, effector function and trafficking8-10.
As most of the signaling pathways that regulate antigen/costimulation-driven T cell recruitment converge on molecular mediators of T cell metabolism (mTOR, Akt), we are currently actively investigating whether and how energy metabolism can fuel T cell trafficking in physiology and pathology.
1. Marelli-Berg FM, Frasca L, Weng L, et al. Antigen recognition influences transendothelial migration of CD4+ T cells. J Immunol 1999;162:696-703.
2. Marelli-Berg FM, James MJ, Dangerfield J, et al. Cognate recognition of the endothelium induces HY-specific CD8+ T-lymphocyte transendothelial migration (diapedesis) in vivo. Blood 2004;103:3111-3116.
3. Jarmin SJ, David R, Ma L, et al. Targeting T cell receptor-induced phosphoinositide-3-kinase p110delta activity prevents T cell localization to antigenic tissue. J. Clin. Invest. 2008;118:1154-1164.
4. David R, Ma L, Ivetic A, et al. T-cell receptor- and CD28-induced Vav1 activity is required for the accumulation of primed T cells into antigenic tissue. Blood 2009;113:3696-705.
5. Ying H, Fu H, Rose ML, et al. Genetic or pharmaceutical blockade of phosphoinositide 3-kinase p110delta prevents chronic rejection of heart allografts. PloS one 2012;7:e32892.
6. Fu H, Kishore M, Gittens B, et al. Self-recognition of the endothelium enables regulatory T-cell trafficking and defines the kinetics of immune regulation. Nat Commun 2014;5:3436.
7. Mirenda V, Jarmin SJ, David R, et al. Physiological and aberrant regulation of memory T cell trafficking by the costimulatory molecule CD28. Blood 2007;109:2968-2977.
8. Ma L, Mauro C, Cornish GH, et al. Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance. Proceedings of the National Academy of Sciences of the United States of America 2010;107:19461-6.
9. Kishore M, Ma L, Cornish G, et al. Primed T cell responses to chemokines are regulated by the immunoglobulin-like molecule CD31. PloS one 2012;7:e39433.
10. Ma L, Cheung KC, Kishore M, et al. CD31 exhibits multiple roles in regulating T lymphocyte trafficking in vivo. Journal of immunology 2012;189:4104-11.
|Giuseppe Danilo NORATA
Professor of Pharmacology
Department of Pharmacological and Biomolecular Sciences, University of Milan
and Center for the Study of Atherosclerosis, SISA Bassini Hospital Cinisello
B – Italy.
Honorary Senior Lecturer, The Blizard Institute, Barts and The London School
of Medicine & Dentistry. Queen Mary University, London – UK.
Our research activity is devoted to the investigation of the molecular mechanisms involved in vascular and cardiometabolic diseases and their connection with immunometabolism. Our group integrates studies in vitro, in animal models and in humans with a translational approach thanks to the deep interaction between the two core labs: Lab of Lipoproteins, Immunity and Atherosclerosis at the Department of Pharmacological and Biomolecular Sciences, University of Milan and the Lab of Cardiovascular Genetics and Genomics at the Center for The Study of Atherosclerosis at the Bassini Hospital.
One line of research is focused of the study of the role of high density lipoprotein (HDL) in modulating cholesterol availability in immune cells thus influencing their function; a second topic of research is focused on the study of post-prandial hypetrygliceridaemia and metabolic consequences in immune cells; a third line of research, studies the impact of therapies for dyslipidemia on immune cells and a fourth line of research adresses the role of key players of immune response such as pentraxin 3 or fibronectin in relation to metabolic disturbancies including dyslipidemia, obesity and atherosclerosis.
The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism.
Demetz E, Schroll A, Auer K, Heim C, Patsch JR, Eller P, Theurl M, Theurl I, Theurl M, Seifert M, Lener D, Stanzl U, Haschka D, Asshoff M, Dichtl S, Nairz M, Huber E, Stadlinger M, Moschen AR, Li X, Pallweber P, Scharnagl H, Stojakovic T, März W, Kleber ME, Garlaschelli K, Uboldi P, Catapano AL, Stellaard F, Rudling M, Kuba K, Imai Y, Arita M, Schuetz JD, Pramstaller PP, Tietge UJ, Trauner M, Norata GD, Claudel T, Hicks AA, Weiss G, Tancevski I.
Cell Metab. 2014 Nov 4;20(5):787-98.
HDL in innate and adaptive immunity.
Catapano AL, Pirillo A, Bonacina F, Norata GD.
Cardiovasc Res. 2014 Aug 1;103(3):372-83.
Cardiometabolic and immune factors associated with increased common carotid artery intima-media thickness and cardiovascular disease in patients with systemic lupus erythematosus.
Ammirati E, Bozzolo EP, Contri R, Baragetti A, Palini AG, Cianflone D, Banfi M, Uboldi P, Bottoni G, Scotti I, Pirillo A, Grigore L, Garlaschelli K, Monaco C, Catapano AL, Sabbadini MG, Manfredi AA, Norata GD.
Nutr Metab Cardiovasc Dis. 2014 Jul;24(7):751-9.
Long pentraxin 3: experimental and clinical relevance in cardiovascular diseases.
Bonacina F, Baragetti A, Catapano AL, Norata GD.
Mediators Inflamm. 2013;2013:725102. doi: 10.1155/2013/725102.
Prevalence of classical CD14++/CD16- but not of intermediate CD14++/CD16+ monocytes in hypoalphalipoproteinemia.
Sala F, Cutuli L, Grigore L, Pirillo A, Chiesa G, Catapano AL, Norata GD.
Int J Cardiol. 2013 Oct 3;168(3):2886-9. doi: 10.1016/j.ijcard.2013.03.103.
Effector Memory T cells Are Associated With Atherosclerosis in Humans and Animal Models.
Ammirati E, Cianflone D, Vecchio V, Banfi M, Vermi AC, De Metrio M, Grigore L, Pellegatta F, Pirillo A, Garlaschelli K, Manfredi AA, Catapano AL, Maseri A, Palini AG, Norata GD.
J Am Heart Assoc. 2012 Feb;1(1):27-41. doi: 10.1161/JAHA.111.000125.
Antigen-dependent and antigen-independent pathways modulate CD4+CD28null T-cells during atherosclerosis.
Ammirati E, Monaco C, Norata GD.
Circ Res. 2012 Jul 6;111(2):e48-9.
Long pentraxin 3/tumor necrosis factor-stimulated gene-6 interaction: a biological rheostat for fibroblast growth factor 2-mediated angiogenesis.
Leali D, Inforzato A, Ronca R, Bianchi R, Belleri M, Coltrini D, Di Salle E, Sironi M, Norata GD, Bottazzi B, Garlanda C, Day AJ, Presta M.
Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):696-703.
Emerging role of high density lipoproteins as a player in the immune system.
Norata GD, Pirillo A, Ammirati E, Catapano AL.
Atherosclerosis. 2012 Jan;220(1):11-21.
HDLs, immunity, and atherosclerosis.
Norata GD, Pirillo A, Catapano AL.
Curr Opin Lipidol. 2011 Oct;22(5):410-6.
The long pentraxin PTX3: a modulator of the immunoinflammatory response in atherosclerosis and cardiovascular diseases.
Norata GD, Garlanda C, Catapano AL.
Trends Cardiovasc Med. 2010 Feb;20(2):35-40.
Circulating CD4+CD25hiCD127lo regulatory T-Cell levels do not reflect the extent or severity of carotid and coronary atherosclerosis.
Ammirati E, Cianflone D, Banfi M, Vecchio V, Palini A, De Metrio M, Marenzi G, Panciroli C, Tumminello G, Anzuini A, Palloshi A, Grigore L, Garlaschelli K, Tramontana S, Tavano D, Airoldi F, Manfredi AA, Catapano AL, Norata GD.
Arterioscler Thromb Vasc Biol. 2010 Sep;30(9):1832-41.
Deficiency of the long pentraxin PTX3 promotes vascular inflammation and atherosclerosis.
Norata GD, Marchesi P, Pulakazhi Venu VK, Pasqualini F, Anselmo A, Moalli F, Pizzitola I, Garlanda C, Mantovani A, Catapano AL.
Circulation. 2009 Aug 25;120(8):699-708.
Long pentraxin 3, a key component of innate immunity, is modulated by high-density lipoproteins in endothelial cells.
Norata GD, Marchesi P, Pirillo A, Uboldi P, Chiesa G, Maina V, Garlanda C, Mantovani A, Catapano AL.
Arterioscler Thromb Vasc Biol. 2008 May;28(5):925-31.
Leader of Team 1 ‘Biology of Atherothrombosis’ & Professor of Immunology of Denis Diderot University
INSERM UMRS1148, Laboratory for Vascular Translational Science
GH Bichat-Claude Bernard
75877 PARIS Cedex 18 – France
During the last 15 years, we have gained significant insight in the field of immunomodulation of cardiovascular diseases. We were the first to show that atherosclerosis is associated with T cell repertoire disturbances and that Th1 cell responses are pro-atherogenic. We also were the first to characterize the pro-atherogenic effect of the activation of NKT cells. We have demonstrated the existence of self-reactive immune responses B and yet atheroprotective role of the B1 cell compartment. We have also described the macrophage plasticity in experimental atherosclerosis.
We were the first to document the presence of tertiary lymphoid organs (TLOs) in the setting of graft arteriosclerosis. More recently, we have described how these structures can develop around atherosclerotic vessels and have provided compelling evidence that T follicular helper cells operate in these structures.
Our new projects aim at understanding how TLOs impact the biology of the tissue in which they develop, at deciphering why there is a close relationship between these lymphoid tissues and adipose tissue, and at developing pre-clinical and clinical tools to monitor TLOs.
1. Nicoletti, A., S. Kaveri, G. Caligiuri, J. Bariety, and G. K. Hansson. 1998. Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J Clin Invest 102:910-918.
2. Zhou, X., A. Nicoletti, R. Elhage, and G. K. Hansson. 2000. Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 102:2919-2922.
3. Laurat, E., B. Poirier, E. Tupin, G. Caligiuri, G. K. Hansson, J. Bariety, and A. Nicoletti. 2001. In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation 104:197-202.
4. Caligiuri, G., A. Nicoletti, B. Poirier, and G. K. Hansson. 2002. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest 109:745-753.
5. Caligiuri, G., M. Rudling, V. Ollivier, M. P. Jacob, J. B. Michel, G. K. Hansson, and A. Nicoletti. 2003. Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol Med 9:10-17.
6. Caligiuri, G., D. Stahl, S. Kaveri, T. Irinopoulous, F. Savoie, C. Mandet, M. Vandaele, M. D. Kazatchkine, J. B. Michel, and A. Nicoletti. 2003. Autoreactive antibody repertoire is perturbed in atherosclerotic patients. Lab Invest 83:939-947.
7. Tupin, E., A. Nicoletti, R. Elhage, M. Rudling, H. G. Ljunggren, G. K. Hansson, and G. P. Berne. 2004. CD1d-dependent activation of NKT cells aggravates atherosclerosis. J Exp Med 199:417-422.
8. Thaunat, O., A. C. Field, J. Dai, L. Louedec, N. Patey, M. F. Bloch, C. Mandet, M. F. Belair, P. Bruneval, O. Meilhac, B. Bellon, E. Joly, J. B. Michel, and A. Nicoletti. 2005. Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response. Proc Natl Acad Sci U S A 102:14723-14728.
9. Khallou-Laschet, J., G. Caligiuri, E. Groyer, E. Tupin, A. T. Gaston, B. Poirier, M. Kronenberg, J. L. Cohen, D. Klatzmann, S. V. Kaveri, and A. Nicoletti. 2006. The proatherogenic role of T cells requires cell division and is dependent on the stage of the disease. Arterioscler Thromb Vasc Biol 26:353-358.
10. Caligiuri, G., J. Khallou-Laschet, M. Vandaele, A. T. Gaston, S. Delignat, C. Mandet, H. V. Kohler, S. V. Kaveri, and A. Nicoletti. 2007. Phosphorylcholine-targeting immunization reduces atherosclerosis. J Am Coll Cardiol 50:540-546.
11. Khallou-Laschet, J., A. Varthaman, G. Fornasa, C. Compain, A. T. Gaston, M. Clement, M. Dussiot, O. Levillain, S. Graff-Dubois, A. Nicoletti, and G. Caligiuri. 2010. Macrophage plasticity in experimental atherosclerosis. PLoS ONE 5:e8852.
12. Thaunat, O., N. Patey, G. Caligiuri, C. Gautreau, M. Mamani-Matsuda, Y. Mekki, M. C. Dieu-Nosjean, G. Eberl, R. Ecochard, J. B. Michel, S. Graff-Dubois, and A. Nicoletti. 2010. Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J Immunol 185:717-728.
13. Dutertre, C. A., M. Clement, M. Morvan, K. Schakel, Y. Castier, J. M. Alsac, J. B. Michel, and A. Nicoletti. 2014. Deciphering the stromal and hematopoietic cell network of the adventitia from non-aneurysmal and aneurysmal human aorta. PLoS One 9:e89983.
14. Guedj, K., J. Khallou-Laschet, M. Clement, M. Morvan, A. T. Gaston, G. Fornasa, J. Dai, M. Gervais-Taurel, G. Eberl, J. B. Michel, G. Caligiuri, and A. Nicoletti. 2014. M1 macrophages act as LTbetaR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis. Cardiovasc Res 101:434-443.
15. Clement, M., K. Guedj, F. Andreata, M. Morvan, L. Bey, J. Khallou-Laschet, A. T. Gaston, S. Delbosc, J. M. Alsac, P. Bruneval, C. Deschildre, M. Le Borgne, Y. Castier, H. J. Kim, H. Cantor, J. B. Michel, G. Caligiuri, and A. Nicoletti. 2015. Control of the Tfh-GC B Cell Axis by CD8+ Tregs Limits Atherosclerosis and Tertiary Lymphoid Organ Development. Circulation 131:560-570.
Research Director Cardiovascular Immunopathology
INSERM UMRS1148, Laboratory for Vascular Translational Science
GH Bichat-Claude Bernard
75877 PARIS Cedex 18 – France
Trinity Biomedical Sciences Institute School of Biochemistry and
Trinity College Dublin Pearse Street
Dublin 2 – Ireland
Professor of Pathology, Department of Medicine and Surgery,
University of Salerno and Immunology Lab, IEOS-CNR, Naples, Italy.
Honorary Professor, William Harvey Research Institute
Queen Mary University of London – UK
Lymphoid Tissue Development Unit
25, Rue du Dr. Roux
75724 Paris – France
Pro-inflammatory cells expressing the nuclear hormone receptor RORgt play a fundamental role in mucosal and skin defense, as well as in the development of lymphoid tissues. RORgt+ cells are also involved in inflammatory pathologies, such as inflammatory bowel diseases and arthritis, and are the target of a new generation of anti-inflammatory drugs blocking RORgt. RORgt+ cells include innate lymphoid cells (ILCs) that are programmed to induce the development of lymphoid tissues and induce early mucosal and skin immunity against microbes, as well as subsets of T cells, such as Th17 cells that react to microbiota.
We develop mouse models to understand how RORgt+ cells control mucosal and skin immunity, and how they respond to and shape microbiota. More generally, we aim at deciphering the mechanisms of the dialogue between microbiota and pro-inflammatory cells, a dialogue that affects host homeostasis and development of inflammatory pathologies. An important partner in this dialogue is the stromal microenvironment, including vessels, perivascular cells and fibroblasts, which have essential roles in lymphocytes recruitment and survival through expression of adhesion molecules, chemokines and cytokines. When inappropriately activated by injury, specific subsets of stromal cells, such as ADAM12+ perivascular cells, contribute to pathogenesis by exacerbating inflammation and fibrosis. Stromal cells play therefore fundamental roles in homeostasis, inflammation and pathology.
We propose that the lymphocyte-stroma-microbiota trilogy is the functional unit that determines the reactivity of the host to infection, injury and cancer, and drives homeostasis. As perturbation of this trilogy generates inflammation and pathology, we aim at defining the underlying crosstalk and mechanisms in order to develop new avenues for prevention and therapy.
1. S. Dulauroy, S.E. Di Carlo, F. Langa, G. Eberl and L. Peduto. 2012. Lineage tracing of ADAM12+ perivascular cells reveals a dominant pro-fibrotic pathway during acute injury. Nat. Med., 18:1262-1270.
2. M. Cherrier, S. Sawa and G. Eberl. 2012. Notch, Id2 and RORgt sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J. Exp. Med., 209:729-740.
3. S. Sawa, M. Lochner, N. Satoh-Takayama, S. Dulauroy, M. Bérard, M. Kleinschek, D. Cua, J.P. Di Santo and G. Eberl. 2011. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol., 12:320-326.
4. M. Lochner, C. Ohnmacht, L. Presley, P. Bruhns, M. Si-Tahar, S. Sawa and G. Eberl. 2011. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells. J. Exp. Med., 208:125-134.
5. S. Sawa, M. Cherrier, M. Lochner, N. Satoh-Takayama, H.J. Fehling, F. Langa, J.P. Di Santo and G. Eberl. 2010. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science, 330:665-669.
6. G. Eberl. 2010. A new vision of immunity: homeostasis of the superorganism. Mucosal Immunology, 3:450-460.
7. N. Satoh-Takayama, C.A.J. Vosshenrich, S. Lesjean-Pottier, S. Sawa, M. Lochner, F. Rattis, J.J. Mention, K. Thiam, N. Cerf-Bensussan, O. Mandelboim, G. Eberl and J.P. Di Santo. 2008. Microbial flora drives interleukin 22 production in NKp46+ cells that provide innate mucosal immune defense. Immunity, 29:958-970.
8. D. Bouskra, C. Brézillon, M. Bérard, C. Werts, R. Varona, I. Gomperts Boneca, and G. Eberl. 2008. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature, 456:507-510.
9. M. Lochner, L. Peduto, M. Cherrier, S. Sawa, F. Langa, R. Varona, D. Riethmacher, M. Si-Tahar, J.P. Di Santo, and G. Eberl. 2008. In vivo Equilibrium of pro-inflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgt+ T cells. J. Exp. Med., 205:1381-1393.
10. G. Eberl. 2005. Inducible lymphoid tissues in the adult gut: recapitulation of a fetal developmental pathway? Nat. Rev. Immunol., 5:413-420.
Chair, Department of Clinical Pathobiochemistry
University Clinic Dresden
Technische Universität Dresden– Germany
The group of T. Chavakis is interested in cell-cell interactions in immunity, including leukocyte-endothelial interactions in the context of inflammatory disease and metabolic disorders, such as diabetes. Moreover, we study interactions of immune cells within metabolic organs in the context of development of insulin resistance.
We have characterized important players in leukocyte-endothelial adhesion, including pathways for leukocyte recruitment in the course of diabetes mellitus. Moreover, we have identified the first endogenous inhibitor of the leukocyte adhesion cascade, the endothelial-derived developmental endothelial locus-1 (Del-1) that antagonizes integrin-dependent leukocyte adhesion and IL-17-dependent inflammatory disease.
Additionally, we study the role of inflammation and immune cells, such as macrophages and T cells in metabolic organs, like the adipose tissue or the liver, for the development of obesity-related metabolic disease (insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease). In this context, we are studying several pathways linking components of innate immunity (such as the complement system, or receptors involved in leukocyte recruitment) or of adaptive immunity (such as the co-stimulatory systems, CD40-CD40L and CD28-B7) to the development of obesity-related insulin resistance and liver disease. Finally, we pursue the bidirectional link between cellular metabolism and function of immune cells.
1. Chavakis, T., et al: The Pattern Recognition Receptor (RAGE) is a Counter-receptor for Leukocyte Integrins: A novel pathway for inflammatory cell recruitment. J. Exp. Med. 198:1507-15, 2003.
2. Orlova, 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.
3. 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.
4. Choi EY…… and Chavakis T. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science, 2008, 322:1101-04.
5. 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 neovascularisation. Nature Medicine, 15:553-8, 2009.
6. Eskan, M.A., Jotwani, R., Abe, T., Chmelar, J., Lim, J.H., Liang, S., Ciero, P., Krauss, J., Li, F., Rauner, M., Hofbauer, L.C., Choi, E.Y., Chung, K.J., Hashim, A., Curtis, M., Chavakis, T.*, Hajishengallis, G.* 2012. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nature Immunology, 13: 465-473, 2012- COVER ARTICLE *contributed equally as senior author to the work
7. Phieler J et al…. and Chavakis T. The complement anaphylatoxin c5a receptor contributes to obese adipose tissue inflammation and insulin resistance. J Immunol. 191: 4367-74, 2013
8. Chatzigeorgiou A …. Chavakis T*, 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 *contributed equally as senior author to the work and corresponding author
9. Chatzigeorgiou A….. and Chavakis T. Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology. 2014; 60: 1196-210
10. Moutsopoulos NM et al….. Chavakis T, Holland SM, Hajishengallis G. Defective Neutrophil Recruitment in Leukocyte Adhesion Deficiency Type I Disease Causes Local IL-17-Driven Inflammatory Bone Loss. Sci Transl Med. 2014 Mar 26;6:229ra40
11. Madhusudhan T et al…. Chavakis T and Isermann B. Defective podocyte insulin signaling throughp85-XBP1 promotes ATF6 dependent maladaptive ER-stress response in diabetic nephropathy. Nature Communications, 2015 Mar 10;6:6496. doi: 10.1038/ncomms7496
|Mihai G Netea
Professor of Medicine
Experimental Internal Medecine
Universitair Medisch Centrum St. Radboud, Faculteit der Medische Wetenschappen
Radboud University Nijmegen, Nijmegen -Netherlands
The group of Mihai Netea is focused on understanding the role of inflammation in the pathogenesis of severe infections in general, and of fungal infections in particular. His team demonstrated the important differences in inflammatory responses between severe bacterial and fungal infection, and they contributed to the concept of adjuvant immunotherapy with recombinant cytokines in the treatment of severe fungal infections.
The research focus of the Netea group spans from to the mechanisms of recognition of pathogenic microorganisms by pattern-recognition receptors, to underatanding the cytokine network that modulates inflammation, and decipher the regulatory networks that decide the functional differentiation of Th1 subsets during infections. His group was the first to demonstrate the specific activation of T-regulatory cells through TLR2, and by employing a combination of genetically-modified Candida strains and receptor knock-out cells they elucidated the precise pathways responsible for the recognition of this pathogen. This led to the first comprehensive model of recognition of a fungal pathogen by the innate immune system.
In addition, the Netea group had an important contribution to the elucidation of the mechanisms responsible for inflammasome activation in various cells types, and especially in the context of activation by fungi. In the last five years research has also focused on the identification of novel immunodeficiencies leading to specific susceptibility to fungal infections. That led to the identification of the first C-type lectin receptor deficiency in patients, and the genetic defect in the autosomal-dominant chronic mucocutaneous candidiasis.
These research lines have been enriched with the understanding that cellular metabolism is a crucial component of the immune response to pathogen. Two recent papers in Science from his group described the important of cellular metabolism of glucose for the adaptive function of innate immunity (trained immunity). In addition, the group of Netea is currently working on understanding the role of immunometabolism during sepsis, as well as for the host defense against fungal and mycobacterial infections.
1. Cheng SC, Quintin J, Cramer RA, … , Stunnenberg HG, Xavier RJ, Netea MG. mTOR/HIF1-mediated aerobic glycolysis as metabolic basis for trained immunity. Science, 2014, 345: 1250684
2. Saeed S, Quintin J, Kerstens HHD, … , Xavier RJ, Logie C, Netea MG, Stunnenberg HG. Epigenetic programming during monocyte to macrophage differentiation and trained innate immunity. Science, 2014, 345: 1251086
3. Cheng SC, Joosten LA, Netea MG. The interplay between central metabolism and innate immune responses. Cytokine Growth Factor Rev. 2014 Dec;25(6):707-13
4. Kumar V, Cheng SC, Johnson MD, … , Xavier RJ, Kullberg BJ, Wijmenga C, Netea MG. Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidemia. Nature Communic, 2014, 5:4675
5. Laayouni H, Oosting M, Luisi P, Ioana M, Alonso S, Ricaño-Ponce I, Trynka G, Zhernakova A, Plantinga T, Cheng SC, van der Meer JWM, Thelma BK, Popp R, Sood A, Wijmenga C, Joosten LAB, Bertranpetit J, Netea MG. Convergent evolution in European and Rroma populations: pressure exerted by plague on Toll-like receptors. Proc Nat Acad Sci USA, 2014, 111:2668-73
6. Quintin J, Saeed S, Martens JH, Giamarellos-Bourboulis EJ, Ifrim DC, Logie C, Jacobs L,
Jansen T, Kullberg BJ, Wijmenga C, Joosten LA, Xavier RJ, van der Meer JW, Stunnenberg HG, Netea MG. Candida albicans Infection Affords Protection against Reinfection via Functional Reprogramming of Monocytes. Cell Host Microbe. 2012;12:223-32.
7. van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, Arts P, Rosentul DC, Carmichael AJ, Smits-van der Graaf CA, Kullberg BJ, van der Meer JW, Lilic D, Veltman JA, Netea MG. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011 Jul 7;365(1):54-61
8. Netea MG, Quintin J, van der Meer JW. Trained immunity: a memory for innate host defense. Cell Host Microbe. 2011 May 19;9(5):355-61.
9. Bart Ferwerda, Gerben Ferwerda, Theo S. Plantinga, Janet A. Willment, Annemiek B. van Spriel, Hanka Venselaar, Clara C. Elbers, Melissa D. Johnson, Alessandra Cambi, Cristal Huysamen, Liesbeth Jacobs, Trees Jansen, Karlijn Verheijen, Laury Masthoff, Servaas A. Morre, Gert Vriend, David L. Williams, John R. Perfect, Leo A.B. Joosten, Cisca Wijmenga, Jos W.M. van der Meer, Gosse J. Adema, Bart-Jan Kulberg, Gordon D. Brown, Netea MG. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med, 2009, 361;1760-7