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Triantafyllos Chavakis
Regulation of vascular inflammation in immunity and the crosstalk between inflammation and angiogenesis
Previous and current research
(1) Leukocyte-endothelial interactions in immunity
Leukocytes follow inflammatory stimuli derived from inflamed, injured or infected tissues, and extravasate to the site of inflammation. The process of leukocyte extravasation involves a cascade of interactions between leukocytes and endothelial cells. These steps include: (I) Rolling: Leukocytes firstly roll along the endothelium in a manner that is dependent on selectin-mediated interactions. (II) Activation Leukocytes are activated by chemokines which are present on the luminal endothelial cell surface. Leukocyte activation involves the activation of integrins on the leukocyte surface. (III) Adhesion: Leukocytes firmly adhere onto endothelial cells. Firm adhesion is dependent on leukocyte beta1- and beta2-integrins, such as VLA-4 (alpha4beta1) or Mac-1 (CD11b/CD18; alphaMbeta2) and LFA-1 (CD11a/CD18; alphaLbeta2). LFA-1 and Mac-1 interact with ICAM-1 and ICAM-2 on endothelial cells, whereas RAGE is another ligand of Mac-1 mediating leukocyte-endothelial adhesion leukocyte recruitment especially under diabetic conditions. Moreover, endothelial-adherent platelets may interact with circulating leukocytes thereby promoting leukocyte recruitment. (IV) Thereafter, adherent leukocytes migrate through the endothelium. The major barrier for the transmigrating leukocyte is formed by endothelial adherens and tight junctions. Transmigration is mediated by homophilic interactions of PECAM-1 as well as by heterophilic interactions of leukocyte integrins with junctional adhesion molecules (JAM), e.g. JAM-A is a ligand of LFA-1 and JAM-C on interacts with leukocyte Mac-1. In addition, JAM-C acts to disrupt the endothelial barrier through blocking VE-cadherin-mediated adherens junctions.
Our group focuses on the regulation of integrin-dependent leukocyte-endothelial adhesion and on the modulation of the endothelial barrier during transmigration (figure). (I) We have identified the anti-adhesive functions of the Staphylococcus aureus-derived factor, Extracellular Adherence Protein (Eap) that can block beta2-integrin-dependent adhesion, thereby helping bacteria to evade the immune response of the host. (II) We have characterized a pathway relevant to leukocyte recruitment in diabetic vascular complications. This pathway involved the interaction of leukocyte Mac-1 with RAGE. (III) We recently, discovered a novel endogenous inhibitor of beta2-integrin-mediated leukocyte adhesion, the endothelial-derived and secreted molecule Developmental endothelial locus-1 (Del-1), which may be of enormous therapeutic importance for interfering with inflammatory cell recruitment. (IV) We have studied the regulation of LFA-1-dependent adhesion and recruitment by the ubiqutin ligase cbl-b and 14-3-3 adpater proteins. (V) We have characterized JAM-C as a counter-receptor for the integrin Mac-1 thereby mediating leukocyte-platelet interactions and leukocyte transmigration. Furthermore, we found that JAM-C disrupts the endothelial barrier by inhibiting VE-cadherin-dependent adherens junctions.
(2) The crosstalk between inflammation and postnatal angiogenesis
Postnatal angiogenesis is relevant in malignant and inflammatory disorders, as well as in the course of eye disease (proliferative diabetic retinopathy, choroideal neovascularization during adult-related macula degeneration). Angiogenesis may be regulated by inflammation and inflammatory cells. Our group studies the crosstalk between components of the innate immunity, such as the antimicrobial defensins, the complement system or macrophages, and neovascularisation especially in the context of retina angiogenesis. In addition, we are interested in the regulation of vascular homeostasis and the pathways involved in endothelial survival. We recently uncovered a link between pathways that signal DNA damage and mediate DNA-repair and hypoxia-induced neovascularisation during proliferative retinopathies.
Future prospects 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.
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Selected publications
Histone H2AX is integral to hypoxia-driven neovascularization Economopoulou M, Langer HF, Celeste A, Orlova VV, Choi EY, Ma M, Vassilopoulos A, Callen E, Deng C, Bassing CH, Boehm M, Nussenzweig A, Chavakis T.Nat Med. 2009 May;15(5):553-8.
Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Choi EY, Chavakis E, Czabanka MA, Langer HF, Fraemohs L, Economopoulou M, Kundu RK, Orlandi A, Zheng YY, Prieto DA, Ballantyne CM, Constant SL, Aird WC, Papayannopoulou T, Gahmberg CG, Udey MC, Vajkoczy P, Quertermous T, Dimmeler S, Weber C, Chavakis T. Science. 2008 Nov 14;322(5904):1101-4.
A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin Orlova VV, Choi EY, Xie C, Chavakis E, Bierhaus A, Ihanus E, Ballantyne CM, Gahmberg CG, Bianchi ME, Nawroth PP, Chavakis T. EMBO J. 2007 Feb 21;26(4):1129-39.
Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin-mediated cell-cell contact Orlova VV, Economopoulou M, Lupu F, Santoso S, Chavakis T. J Exp Med. 2006 Nov 27;203(12):2703-14.
Staphylococcus aureus extracellular adherence protein serves as anti-inflammatory factor by inhibiting the recruitment of host leukocytes. Chavakis T, Hussain M, Kanse SM, Peters G, Bretzel RG, Flock JI, Herrmann M, Preissner KT. Nat Med. 2002 Jul;8(7):687-93.