Regulation of vascular inflammation in immunity and metabolic disease
Previous and Current Research
The scientific focus of our group is at the crossroads of Immunology, Inflammation, Vascular Medicine and Metabolism; we try to merge Basic Science and Translational Medicine by engaging preclinical translational animal models. We aim at identifying the role of mechanisms pertinent to immunology and vascular inflammation, especially leukocyte recruitment and activation, in the regulation of metabolic pathologies, such as the development of insulin resistance and type 2 diabetes mellitus, the vascular complications of diabetes mellitus, especially diabetic retinopathy, as well as in inflammatory and autoimmune disorders.
(A) Cellular and molecular mechanisms of immune cell recruitment and activation in inflammatory and metabolic disease.
Our group studies the molecular mechanisms governing leukocyte-endothelial interactions in the course of metabolic, inflammatory disorders and autoimmune conditions (e.g. experimental autoimmune encephalomyelitis/multiple sclerosis). (i) We identified the anti-adhesive and anti-inflammatory functions of the Staphylococcus aureus-derived factor, Extracellular Adherence Protein (Eap) and contributed to the understanding how bacteria subvert the host immune response. (ii) We have characterized a novel component of endothelial junctions, Junctional Adhesion Molecule-C (JAM-C). JAM-C is a critical player during leukocyte transendothelial migration. (iii) Our work recently 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 to the endothelium and IL-17-dependent inflammation. (iv) We characterized new pathways for leukocyte recruitment in the course of diabetes mellitus and in diabetic vascular complications based on interactions of leukocyte integrin Mac-1 with the Receptor for advanced glycation endproducts. (v) We have identified an important role for platelets in mediating leukocyte recruitment in the course of neuroinflammation.
(B) Immunometabolism: Cellular and molecular mechanisms of the crosstalk between inflammation and metabolism.
Emerging evidence points to a major role of inflammation and immune cells, such as macrophages and T cells in metabolic organs, such as the adipose tissue or the liver for the development of obesity-related metabolic disease, such as 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, macrophage polarisation 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.
(C) Crosstalk between inflammation and neovascularisation in retina disease, including diabetic retinopathy and retinopathy of prematurity.
(i) In this context we have demonstrated the angiogenesis-modulatory actions of components of the innate immunity, such as neutrophil-derived alpha-defensins, or the complement system and in particular, the anaphylatoxin C5a receptor. (ii) In addition, we have uncovered the first link between pathways that signal DNA damage and mediate DNA-repair and hypoxia-induced neovascularisation in the course of proliferative retinopathies. We currently expand on these findings by analysing further pathways that mediate the response to cellular stress in endothelial cells in the course of vasoproliferative retina disease.
Future Projects and Goals
We are trying to understand the connection between inflammation and metabolism. In particular, we plan to study the cellular and molecular mechanisms underlying inflammatory cell recruitment to the adipose tissue in the course of obesity and in diabetes mellitus. Moreover, we will continue analyzing the role of leukocyte-endothelial interactions in innate and adaptive immunity. Furthermore, we will expand on studies related to the regulation of vascular homeostasis, as well as related to the regulation of inflammation by angiogenesis.
Methodological and Technical Expertise
1) Mouse models of disease
- acute Inflammation: lung inflammation, peritonitis, vasculitis, SIRS-sepsis
- autoimmunity: experimental autoimmune encephalomyelitis
- diet-induced obesity, insulin resistance, non-alcoholic fatty liver disease
- Proliferative Retinopathy – Angiogenesis
- Intravital mouse microscopy currently being set up
In most of these models tissue analysis by:
- real-time RT-PCR
- flow cytometry analysis of primary cells
2) Generation and utilization of genetically modified mice: Molecular cloning
3) Isolation of primary cell populations (bone marrow cells, endothelial cells, micoglia cells)
4) Cell-Cell adhesion and Cell-Matrix adhesion; Leukocyte adhesion, Leukocyte migration, Leukocyte activation, Macrophage polarization
5) Biochemistry: Western Blot, IP
6) Fluorescent immunocytochemistry – confocal microscopy
Choi EY, Chavakis E, Czabanka MA, Langer H, Fraemohs L, Economopoulou M, Kundu RK, Orlandi A, Zheng YY, Prieto DA, Ballantyne CM, Constant SL, Aird W, Papayannopoulou T, Gahmberg CG, Udey MC, Vajkoczy P, Quertermous T, Dimmeler S, Weber C, and Chavakis T.
Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment.
Science, 322:1101-04 (2009)
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)
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.*
The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss.
Nature Immunology, 13: 465-473, COVER ARTICLE (2012)
*contributed equally as senior authors to the work
Langer, H.F., Choi, E.Y., Zhou, H., Schleicher, R., Chung, K.J., Tang, Z., Göbel, K., Bdeir, K., Chatzigeorgiou, A., Wong, C., Bhatia, S., Kruhlak, M.J., Rose, J., 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.
Circulation Research, 110:1202-10 (2012)
Chatzigeorgiou A, Chung KJ, Garcia-Martin R, Alexaki I, … Karalis KP, Lutgens E, and Chavakis T.
Dual role of B7 costimulation in obesity-related non-alcoholic steatohepatitis (NASH) and metabolic dysregulation.
Hepatology (Epub ahead of print) (2014)