Junior group 'Systemic inflammation and vascular disease'
Susanne Karbach, MD
Junior group leader
The junior group has the scientific focus on the role of systemic inflammation in the development of vascular disease. Deep vein thrombosis (DVT) and the sequel venous thromboembolism are – besides cardiovascular disease - major causes of death worldwide. Thrombus formation is associated with inflammation – and inflammation can be both a cause and a consequence of VTE, showing the high demands on current anticoagulant therapy. During thrombus generation and resolution, immune cells play a pivotal role: A crosstalk between monocytes/macrophages, neutrophil granulocytes, and platelets was described to be relevant in the initiation and amplification of deep vein thrombosis. Not only innate immune cells, but also effector memory T-cells have been reported to be relevant in the inflammatory response in venous thrombosis affecting thrombus resolution. We could show that venous thrombus resolution was accelerated in the setting of depletion of the myelomonocytic cells.
IL-6 is a cytokine which is extremely relevant within the immune response, especially concerning the switch from the innate to the adaptive immune response. It is secreted by monocytes, macrophages, endothelial cells, fibroblasts and partially also by neutrophil granulocytes, leads to neutrophil recruitment and stimulates IL-17A production by CD4+ T-cells (Th17 cell differentiation) which also – amongst other effects - results in myelomonocytic cell recruitment. Due to its central role within the immune response, IL-6 is important in the context of vascular inflammation, vascular dysfunction and hypertension as well as in the development of cardiovascular disease. IL-6 also appears to be relevant in linking inflammation, coagulation and thrombosis: It accelerates arterial thrombosis formation when secreted by alveolar macrophages after exposition to particulate matter leading to reduced clotting time and leads to increased platelet activation in experimental colitis. IL-6 can directly increase platelet responsiveness to thrombin-induced activation, increase tissue factor (TF) expression and the TF surface expression on monocytes, stimulates thrombopoiesis through thrombopoietin and leads to hyper-activation of platelets. We are analyzing mice that overexpress IL-6 in myelomonocytic cells (LysM-IL-6ind/+ mice) concerning thrombus development in the inferior vena cava stenosis model.
Better understanding of the inflammatory mechanisms behind thrombosis development is necessary for future anticoagulant therapy and we aim to investigate the role of IL-6 and associated cytokines in the development of thrombosis also focusing on the interplay of neutrophils, monocyte/macrophage, platelet and the vessel wall.
- Inflammatory mechanisms in deep vein thrombosis
- Role of IL-6 and IL-6-induced cytokines for the interaction of cells and factors of the immune system and blood coagulation
- Analysis of IL-6 and inflammatory markers in DVT patient and corellation with diesease development and outcome
Partners of collaboration
Partners at the University Medical Center Mainz
- Prof. Philip Wenzel (CTH)
- Prof. Ari Waisman (Institute for Molecular Medicine)
- Prof. Andreas Daiber (Center for Cardiology – Cardiology I)
- Prof. Bernhard Lämmle as senior professor (CTH)
- PD Dr. Kerstin Jurk (CTH)
- Prof. Wolfram Ruf (CTH)
- Jun.-Prof. Christoph Reinhardt (CTH)
- PD Dr. Mareike Lankeit, Dr. Lukas Hobohm (CTH)
- Prof. Huige Li (Department of Pharmacology)
- Prof. Dr. Ellen Closs (Department of Pharmacology)
- Prof. Dr. Markus Radsak (3rd Medical Department, Institute for Immunology)
- Prof. Christine Espinola-Klein (Center for Cardiology, Cardiology I - Angiology)
- Prof. Jens Titze (Vanderbilt University, Nashville, USA)
- Prof. Dominik Müller (Max-Delbrück-Center of Molecular Medicine, Berlin)
- Dr. Henry Spronk (CARIM, Maastricht, the Netherlands)
- Prof. Thomas Korn (Experimental Neuroimmunology TU Munich)
- Prof. Ingo Bechmann (Institute of Anatomy, University of Leipzig)
Third party funding
- BMBF (CTH, 01EO1503)
- DFG (KA 4035/1-1)
- Boehringer Ingelheim Foundation
The work group of Susanne Karbach is looking for motivated students who want to perform their master thesis.
Find a more detailed description here (Pdf-file, 61,0 KB).
Team - Junior group 'Systemic inflammation and vascular disease'
- Schüler R, Brand A, Klebow S, Wild J, Veras FP, Ullmann E, Roohani S, Kolbinger F, Kossmann S, Wohn C, Daiber A, Münzel T, Wenzel P, Waisman A, Clausen BE, Karbach S. Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis. J Invest Dermatol 2019;139(3):638-647.
- Karbach S, Lagrange J, Wenzel P. Thromboinflammation and Vascular Dysfunction. Hamostaseologie 2018.
- Brandt M, Giokoglu E, Garlapati V, Bochenek ML, Molitor M, Hobohm L, Schönfelder T, Münzel T, Kossmann S, Karbach SH, Schäfer K, Wenzel P. Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase-Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice. Oxid Med Cell Longev 2018;2018:1860513.
- Schönfelder T, Brandt M, Kossmann S, Knopp T, Münzel T, Walter U, Karbach SH, Wenzel P. Lack of T-bet reduces monocytic interleukin-12 formation and accelerates thrombus resolution in deep vein thrombosis. Sci Rep 2018;8(1):3013.
- Kossmann S, Lagrange J, Jäckel S, Jurk K, Ehlken M, Schönfelder T, Weihert Y, Knorr M, Brandt M, Xia N, Li H, Daiber A, Oelze M, Reinhardt C, Lackner K, Gruber A, Monia B, Karbach SH, Walter U, Ruggeri ZM, Renne T, Ruf W, Münzel T, Wenzel P (2017) Platelet-localized fxi promotes a vascular coagulation-inflammatory circuit in arterial hypertension. Science translational medicine 9
- Karbach SH, Schönfelder T, Brandao I, Wilms E, Hormann N, Jäckel S, Schuler R, Finger S, Knorr M, Lagrange J, Brandt M, Waisman A, Kossmann S, Schäfer K, Münzel T, Reinhardt C, Wenzel P (2016) Gut microbiota promote angiotensin ii-induced arterial hypertension and vascular dysfunction. Journal of the American Heart Association 5
- Klebow S, Hahn M, Nikoalev A, Wunderlich FT, Hövelmeyer N, Karbach* SH, Waisman* A (2016) Il-6 signaling in myelomonocytic cells is not crucial for the development of imq-induced psoriasis. PloS one 11:e0151913
- Uluckan O, Jimenez M, Karbach S, Jeschke A, Grana O, Keller J, Busse B, Croxford AL, Finzel S, Koenders M, van den Berg W, Schinke T, Amling M, Waisman A, Schett G, Wagner EF (2016) Chronic skin inflammation leads to bone loss by il-17-mediated inhibition of wnt signaling in osteoblasts. Science translational medicine 8:330ra337
- Wenzel P, Rossmann H, Müller C, Kossmann S, Oelze M, Schulz A, Arnold N, Simsek C, Lagrange J, Klemz R, Schönfelder T, Brandt M, Karbach SH, Knorr M, Finger S, Neukirch C, Hauser F, Beutel ME, Kröller-Schön S, Schulz E, Schnabel RB, Lackner K, Wild PS, Zeller T, Daiber A, Blankenberg S, Münzel T (2015) Heme oxygenase- 1 suppresses a pro-inflammatory phenotype in monocytes and determines endothelial function and arterial hypertension in mice and humans. Eur Heart J 36:3437-3446
- Croxford* AL, Karbach* S, Kurschus FC, Wörtge S, Nikolaev A, Yogev N, Klebow S, Schüler R, Reissig S, Piotrowski C, Brylla E, Bechmann I, Scheller J, Rose-John S, Wunderlich FT, Münzel T, von Stebut E, Waisman A (2014) Il-6 regulates neutrophil microabscess formation in IL-17a-driven psoriasiform lesions. J Invest Dermatol 134:728-735
- Karbach S, Croxford AL, Oelze M, Schüler R, Minwegen D, Wegner J, Koukes L, Yogev N, Nikolaev A, Reissig S, Ullmann A, Knorr M, Waldner M, Neurath MF, Li H, Wu Z, Brochhausen C, Scheller J, Rose-John S, Piotrowski C, Bechmann I, Radsak M, Wild P, Daiber A, von Stebut E, Wenzel P, Waisman A, Münzel T (2014) Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease. Arterioscler Thromb Vasc Biol 34:2658-2668
- Karbach S, Wenzel P, Waisman A, Münzel T, Daiber A (2014) Enos uncoupling in cardiovascular diseases--the role of oxidative stress and inflammation. Current pharmaceutical design 20:3579-3594
- El Malki* K, Karbach* SH, Huppert* J, Zayoud M, Reissig S, Schüler R, Nikolaev A, Karram K, Münzel T, Kuhlmann CR, Luhmann HJ, von Stebut E, Wörtge S, Kurschus FC, Waisman A (2013) An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling. J Invest Dermatol 133:441-451
- Simon* A, Karbach* S, Habermeier A, Closs EI (2013) Decoding the substrate supply to human neuronal nitric oxide synthase. PloS one 8:e67707
- Karbach S, Jansen T, Horke S, Heeren T, Scholz A, Coldewey M, Karpi A, Hausding M, Kröller-Schön S, Oelze M, Münzel T, Daiber A (2012) Hyperglycemia and oxidative stress in cultured endothelial cells--a comparison of primary endothelial cells with an immortalized endothelial cell line. J Diabetes Complications 26:155-162
- Wenzel P, Knorr M, Kossmann S, Stratmann J, Hausding M, Schuhmacher S, Karbach SH, Schwenk M, Yogev N, Schulz E, Oelze M, Grabbe S, Jonuleit H, Becker C, Daiber A, Waisman A, Münzel T (2011) Lysozyme m-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction. Circulation 124:1370-1381
- *contributed equally