AG Differentiation and Activation of Macrophages
AG Leiter Dr. Alexei Gratchev

AG Cell and Molecular Biology of Innate Immunity
AG Leiterin PD. Dr. Julia Kzhyshkowska 

AG Tumour Associated Macrophages 
AG Leitung Dr. Astrid Schmieder, Prof. Dr. Sergij Goerdt

Dinara Nurgazieva Doctoral student
Hiltrud Schönhaber MTA 
Bärbel Schleider MTA

Isabell Muller-Molinet MD
Sheila Kannookadan MD
Miriam Ochsenreiter MD
Giovanni Frongia MD
Kirsten Köthe MD
Jochen Utikal MD
Wen Ming
Anna Popova PhD

Macrophages are essential elements of the immune system that orchestrate activation and down-regulation of inflammatory reactions, tissue remodelling, healing processes and tissue homeostasis. Macrophages play an important role in pathogenesis of various chronic inflammatory diseases and tumours. Depending on differentiation conditions macrophages acquire a wide variety of functions. These functional states are maintained by unique molecular repertoires. According to their ability to regulate inflammatory reaction macrophages were classified into 2 major types. Type 1 macrophages (M1) are pro-inflammatory and may be induced by various endo- and exogenous stimuli e.g. IFN-gamma, lipopolysaccharide, myramildipeptid. Type 2 macrophages (M2) do not have pro-inflammatory properties and may be induced by IL-4, IL-13, IL-10, TGF-beta or glucocorticoids. Systematic analysis of M2 macrophages revealed that every stimulus used induces a specific macrophage phenotype with unique functional properties (Figure 1). While the complexity of the system is already high enough due to the existence of alternative signalling pathways and feed back loops induced by a single factors, in the physiological situation the cooperation between several factors as well as sequence of stimulations play important roles. This complexity of the system makes it virtually impossible to asses the impact of every particular molecular event using classical molecular biological methodology. Mathematical modelling of signalling using frameworks of differential equations will allow qualitative and quantitative description of macrophage behaviour in conditions simulating physiological situation. Although the model construction requires large amounts of quantitative experimental data, the analysis of the model using mathematical methods enables the identification of the elements critical for the system. Mathematical modelling allows optimisation of experimental procedures and points the gaps in our knowledge about the mechanisms of macrophage differentiation and activation.

Our current research is focused on molecular mechanisms of macrophage differentiation and activation. Using experimental system based on primary human monocyte derived macrophages we study signalling pathways and transcription factors activated by Th2 associated cytokines, TGF-beta and glucocorticoids and their impact on different physiological and pathological situations. In cooperation with mathematicians we develop mathematical models of investigated pathways to be able to identify parameters of the system that cannot be measured.

Prof. Dr. A.N. Orekhov, Cardiologic Centre, Russian Academy of Medical Sciences, Moscow, Russia 
Prof. Dr. F.L. Kisseljov, Russian Cancer Research Centre, Russian Academy of Medical Sciences, Moscow, Russia 
Prof. Dr. A.A. Romanjukha, Institute for Applied Mathematics, Russian Academy of Sciences, Moscow, Russia
Dr. A. Marcinjak-Cochra, Institute for Applied Mathematics, University of Heidelberg, Heidelberg, Germany

1.    Zhang J*, Gratchev A*, Riabov V, Mamidi S, Schmuttermaier C, Krusell L, Kremmer E, Workman G, Sage EH, Jalkanen S, Goerdt S, Kzhyshkowska J. A novel GGA-binding site is required for intracellular sorting mediated by stabilin-1. Mol Cell Biol. 2009 Nov;29(22):6097-105.

2.    Park SY, Jung MY, Lee SJ, Kang KB, Gratchev A, Riabov V, Kzhyshkowska J, Kim IS Stabilin-1 mediates phosphatidylserine-dependent clearance of cell corpses in alternatively activated macrophages. J Cell Sci. 2009 Sep 15;122(Pt 18):3365-73.

3.     Gratchev A*,  Kzhyshkowska J*, Kannookadan S, Ochsenreiter M, Popova A, Yu X, Muller-Molinet I, Gooi LM, Goerdt S. Activation of a TGF-beta-specific multistep gene expression program in mature M2 macrophages requires glucocorticoid-mediated surface expression of TGF-beta receptor II. Journal of Immunology. 2008;180(10):6553-65.

4.    Kzhyshkowska J*, Gratchev A*, Schmuttermaier C, Brundiers H, Krusell L, Mamidi S, Zhang J, Workman G, Sage EH, Anderle C, Sedlmayr P, and Goerdt S. Alternatively activated macrophages regulate extracellular levels of the hormone placental lactogen via receptor-mediated uptake and transcytosis. J  Immunol. 180(5):3028-37.

5.    Kzhyshkowska J, Marciniak-Czochra A, Gratchev A. Perspectives of mathematical modelling for understanding of intracellular signalling and vesicular trafficking in macrophages. Immunobiology. 2007;212(9-10):813-25.

6.    Booken N*, Gratchev A*, Utikal J, Weiss C, Yu X, Qadoumi M, Schmuth M, Sepp N, Nashan D, Rass K, Tüting T, Assaf C, Dippel E, Stadler R, Klemke CD, Goerdt S. Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3. Leukemia. 2008; 22(2):393-9.

7.    Gratchev A, Kzhyshkowska J, Kothe K, Muller-Molinet I, Kannookadan S, Utikal J, Goerdt S. Mphi1 and Mphi2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals. Immunobiology. 2006;211(6-8):473-86.

8.    Utikal J*, Gratchev A*, Muller-Molinet I, Oerther S, Kzhyshkowska J, Arens N, Grobholz R, Kannookadan S, Goerdt S. The expression of metastasis suppressor MIM/MTSS1 is regulated by DNA methylation. Int J Cancer. 2006;119(10):2287-93.

9.    Kzhyshkowska J, Workman G, Cardo-Vila M, Arap W, Pasqualini R, Gratchev A, Krusell L, Goerdt S, Sage EH. Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. J Immunol. 2006;176(10):5825-32.

10. Kzhyshkowska J*, Mamidi S*, Gratchev A, Kremmer E, Schmuttermaier C, Krusell L, Haus G, Utikal J, Schledzewski K, Scholtze J, Goerdt S. Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is upregulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood. 2006;107(8):3221-8.

11. Martens J-H*, Kzhyshkowska J*, Falkowski-Hansen M, Schledzewski K, Gratchev A, Mansmann U, Schmuttermaier C, Dippel E, Koenen W, Riedel F, Sankala M, Tryggvason K, Kobzik L, Moldenhauer G, Arnold B, Goerdt S. Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis. J Path. 2006;208: 574-89.

12. Kzhyshkowska J, Gratchev A, Martens J-H, Pervushina O, Mamidi S, Johansson S, Schledzewski K, Hansen B, He K, Tang J, Gordon S, Nakayama K, Goerdt S. Stabilin-1 localises to endosomes and the trans-Golgi network in human macrophages and interacts with GGA adaptors. J Leuk Biol, 2004; 76(6):1151-61.

JingJing Zhang PhD student. Phone 383 3945
Vladimir Riabov, PhD student. Phone 383 3945
Illya Ovsiy, PhD student. Phone 383 3945
Nan Wang, PhD student. Phone 383 3945
Christina Schmuttermaier, Technical assistant. Phone 383 3945

Berit Hansen, postdoc
Jan-Henning Martens, postdoc
Olga Pervushina, posdoc
Srinivas Mamidi, PhD student
Liis Krusell, PhD student
Antje Dittmann, Master Student
Heike Brundiers, Diploma student
LiMing Gooi, Bachelor student
Stefanie Huck, undergraduate student

 

Macrophages are essential immune regulatory cells which coordinate defense against pathogens, resolution of inflammation and healing of wounds, and control immunotolerance in healthy adult tissues and in development. Pathological signaling in macrophages results in chronic inflammation, tumor immune escape and progression of neurodegenerative diseases. The major aim of my research is to understand receptor-mediated mechanisms of macrophage function so that the desirable activities can be promoted, and the undesirable activities that cause disease can be controlled. 

Numerous cytokines and hormones control activation and polarization of macrophages. Macrophages respond to the stimulation by production of cytokines, growth factors, enzymes and components of extracellular matrix. At the same time macrophages internalize and process both pathogens and “unwanted-self” components, and that is an essential part of their homeostatic, their immune and their destructive activities. When macrophages internalize different kinds of extracellular ligands, they sort them into different vesicular trafficking pathways.

Trafficking processes include receptor-mediated recognition and internalization of pathogens, dying cells, proteins or lipoproteins, targeting of these ligands for degradation, receptor recycling to the cell surface, secretion and transcytosis (traveling in vesicles through the cell). Consequently, macrophages control differentiation and activation of various cell types by secretion of newly synthesized products or products which they have internalized and modified.

The basic research program has two major directions: 1) dissection of receptor-mediated mechanisms that determine pro-inflammatory versus tolerogenic programming of macrophages: cross-talk between intracellular trafficking and signal transduction (Figure 1); and 2) functional and biochemical characterization of novel macrophage-derived effector molecules and intracellular processes that implicate in pathogen recognition and control inflammation and immunotolerance.

We have identified that stabilin-1, that is specifically expressed on tolerogenic macrophage subpopulations uniquely combines both clearance and intracellular sorting function in macrophages (Figure 2). We found that stabilin-1 is responsible for the delivery of novel chitinase-like protein SI-CLP from the biosynthetic Golgi compartment to the secretory lysosomes. Searching for the intracellular molecular sorting machinery that is used by stabling-1 we have identified its interaction with GGA adaptors (Figure 3) and with novel synaptotagmin-like protein SI-Syt. Function of these sorting systems in macrophages as well as biological activity of chitinase-like protein SI-CLP are currently under investigation.

 

Original articles

1.       Popova A, Kzhyshkowska J, Goerdt S, Gratchev A. IFNgamma and IL-4 control macrophage differentiation by inducing autocrine CSF1 production and dexamethasone by stimulation of surface exposure of CSF1R. Immunobiology, in press.

2.       Fuentes-Duculan J, Suárez-Fariñas M, Zaba LC, Nograles KE, Pierson KC, Mitsui H, Pensabene CA, Kzhyshkowska J, Krueger JG, Lowes MA. Subpopulations of CD163 positive macrophages are classically activated in psoriasis. J Invest Dermatol. 2010 Jun 17. [Epub ahead of print]

3.       Werno C, Menrad H, Weigert A, Dehne N, Goerdt S, Schledzewski K, Kzhyshkowska J, Brüne B. Knockout of Hif-1alpha in tumor-associated macrophages enhances M2 pPlarization and attenuates their pro-angiogenic responses. Carcinogenesis. 2010 Apr 28. [Epub ahead of print]

4.       Zhang J, Gratchev A, Riabov V, Mamidi S, Schmuttermaier C, Krusell L, Kremmer E, Workman G, Sage EH, Jalkanen S, Goerdt S, Kzhyshkowska J. Novel GGA-binding site is required for intracellular sorting mediated by stabilin-1. Mol Cell Biol, 2009 Nov;29(22):6097-105.

5.       Park SY, Jung MY, Lee SJ, Kang KB, Riabov V, Gratchev A, Kzhyshkowska J*, Kim I-S*. Stabilin-1 mediates phosphatidylserine-dependent clearance of cell corpse in alternatively activated macrophages. J Cell Sci. 2009 Sep 15;122(Pt 18):3365-73 (*equal last authorship)

6.       Karikoski M,  Irjala H, Maksimow M, Miiluniemi M, Granfors K, Hernesniemi S, Elima K, Moldenhauer G, Schledzewski K, Kzhyshkowska J, Goerdt S, Salmi M, and Jalkanen S. Clever-1/Stabilin-1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation. Eur J Immun, 2009 2009 Dec;39(12):3477-87

7.       Mosig S, Rennert K, Krause S, Kzhyshkowska J, Neunübel K, Heller R, and Funke H. Different functions of CD14⁺⁺CD16^- and CD14⁺CD16⁺ monocyte subsets in the handling of LDL in patients with Familial Hypercholesterolemia: Potential Function of CD1⁴⁺CD1⁶⁺ monocytes in detoxification of oxidized LDL. FASEB Journal, 2009 Mar;23(3):866-74

8.        Gratchev A*, Kzhyshkowska J*, Kannookadan S, Ochsenreiter M, Popova A, Yu X, Muller-Molinet I,Gooi LM, Goerdt S. Activation of a TGF-beta-specific multistep gene expression program in mature M2 macrophages requires glucocorticoid-mediated surface expression of TGF-beta receptor II. Journal of Immunology  2008 May 15;180(10):6553-65 (*equal contribution)

9.       Kzhyshkowska J*, Gratchev A*, Schmuttermaier C, Brundiers H, Krusell L, Mamidi S, Zhang J, Workman G, Sage EH, Anderle C, Sedlmayr P, and Goerdt S. Alternatively activated macrophages regulate extracellular levels of the hormone placental lactogen via receptor-mediated uptake and transcytosis. J  Immunol,  2008 Mar 1;180(5):3028-37(*equal contribution)

10.   Klein D, Demory A, Peyre F, Kroll J, Augustin H, Helfrich W, Kzhyshkowska J, Schledzewski K, Arnold B, Goerdt S. Wnt2 acts as a cell type-specific, autocrine growth factor in rat hepatic sinusoidal endothelial cells cross-stimulating the VEGF pathway. Hepatology, 2008 Mar;47(3):1018-31.

11.     Gratchev A, Schmuttermaier C, Mamidi S, Gooi L,Goerdt S, Kzhyshkowska J. Expression of osteoarthritis marker YKL-39 is stimulated by transforming growth factor beta (TGF-beta) and IL-4 in differentiating macrophages. Biomarker Insights, 2008, 39-44.

12.   Kzhyshkowska J*, Mamidi S*, Gratchev A, Kremmer E, Schmuttermaier C, Krusell L, Haus G, Utikal J, Schledzewski K, Scholtze J, Goerdt S. Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood 2006; 107(8):3221-3228 (*equal contribution)

13.   Kzhyshkowska J, Workman G, Cardo-Vila M, Arap W, Pasqualini R, Gratchev A, Krusell L, Goerdt S, Sage EH. Novel function of alternatively activated macrophages: Stabilin-1-mediated clearance of SPARC. J Immunol 2006; 176(10):5825-5832

14.   Luo Q, Nieves E, Kzhyshkowska J, Angeletti RH. EndogenousTGF-beta receptor-mediated smad signaling complexes analyzed by mass spectrometry. Mol Cell Proteomics 2006 Jul;5(7):1245-60.

15.   Martens JH*, Kzhyshkowska J*, Falkowski-Hansen M, Schledzewski K, Gratchev A, Mansmann U, Schmuttermaier C, Dippel E, Koenen W, Riedel F, Sankala M, Tryggvason K, Kobzik L,  Moldenhauer G, Arnold B, Goerdt S. Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis. J Pathol 2006; 208(4):574-589. (*equal contribution)

16.   Schledzewski K*, Falkowski M*, Moldenhauer G, Metharom P, Kzhyshkowska J, Ganss R, Demory A, Falkowska-Hansen B, Kurzen H, Ugurel S, Geginat G, Arnold B, Goerdt S. Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1(+), F4/80(+), CD11b(+) macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J Pathol 2006; 209(1):67-77. (*equal contribution)

17.   Utikal J, Gratchev A, Muller-Molinet I, Oerther S, Kzhyshkowska J, Arens N, Grobholz R, Kannookadan S, Goerdt S. The expression of metastasis suppressor MIM/MTSS1 is regulated by DNA methylation. Int J Cancer 2006 Nov 15;119(10):2287-93.

18.   Gratchev A, Kzhyshkowska J, Kothe K, Muller-Molinet I, Kannookadan S, Utikal J, Goerdt S. Mphi1 and Mphi2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals. Immunobiology 2006; 211(6-8):473-486.

19.   Gratchev A, Kzhyshkowska J, Utikal J, Goerdt S. Interleukin-4 and dexamethasone counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages. Scand J Immunol 2005; 61(1):10-17.

20.   Hansen B, Longati P, Elvevold K, Nedredal GI, Schledzewski K, Olsen R, Falkowski M, Kzhyshkowska J, Carlsson F, Johansson S, Smedsrod B, Goerdt S, Johansson S, McCourt P. Stabilin-1 and stabilin-2 are both directed into the early endocytic pathway in hepatic sinusoidal endothelium via interactions with clathrin/AP-2, independent of ligand binding. Exp Cell Res 2005; 303(1):160-173.

21.   Kzhyshkowska J, Gratchev A, Brundiers H, Mamidi S, Krusell L, Goerdt S. Phosphatidylinositide 3-kinase activity is required for stabilin-1-mediated endosomal transport of acLDL. Immunobiology 2005; 210(2-4):161-173.

22.   Kzhyshkowska J, Gratchev A, Martens JH, Pervushina O, Mamidi S, Johansson S Schledzewski K, Hansen B, He X, Tang J, Nakayama K, Goerdt S. Stabilin-1 localizes to endosomes and the trans-Golgi network in human macrophages and interacts with GGA adaptors. J Leukoc Biol 2004; 76(6):1151-1161.

23.   Gratchev A, Kzhyshkowska J, Duperrier K, Utikal J, Velten FW, Goerdt S. The receptor for interleukin-17E is induced by Th2 cytokines in antigen-presenting cells. Scand J Immunol 2004; 60(3):233-237.

24.   Kzhyshkowska J, Kremmer E, Hofmann M, Wolf H, Dobner T. Protein arginine methylation during lytic adenovirus infection. Biochem J 2004; 383(Pt 2):259-265.

25.   Kzhyshkowska J, Rusch A, Wolf H, Dobner T. Regulation of transcription by the heterogeneous nuclear ribonucleoprotein E1B-AP5 is mediated by complex formation with the novel bromodomain-containing protein BRD7. Biochem J 2003; 371(Pt 2):385-393.

26.   Politz O, Gratchev A, McCourt PA, Schledzewski K, Guillot P, Johansson S, Svineng G, Franke P, Kannicht C, Kzhyshkowska J, Longati P, Velten FW, Johansson S, and  Goerdt S. Stabilin-1 and -2 constitute a novel family of fasciclin-like hyaluronan receptor homologues. Biochem J 2002; 362(Pt 1):155-164.

27.   Lebedev I, Bolorma V, Kzhishkovska I, Ostashkin AS, Il'in KV, Miandina GI, Piagai PE, Itkes AV. Integration of the type D Mason-Pfizer monkey virus into the human chromosome. Mol Biol (Mosk) 2002; 36(6):1012-1014

Reviews, book chapters

1.       Kzhyshkowska J. Chitinase-like lectins in humans. Invited book chapter. Nova Science Publishers Inc. N.Y., USA Book title “Binomium Chitin-Chitinase: New
Research with biological, nutritional and health finalities”, 2009.

2.       Kzhyshkowska J, Krusell L. Cross-talk between endocytic clearance and secretion in macrophages. Immunobiology, 2009 Jul;214(7):576-93

3.       Kzhyshkowska J, Gordon S. Editorial for the Immunobiology Special Issue “Vesicular trafficking in immune cells”, 2009 Jul;214(7):493-4

4.       Kzhyshkowska J, Zhang J. GGA1 Targeted Proteins Database 1 (2008), [22660], 10.2970/tpdb.2009.222.

5.       Kzhyshkowska J, The Role of Macrophages in Inflammation and Cancer: New Processes Mediated by Stabilin-1. Akt Dermatol 2008; 34:72-84. In German

6.       Kzhyshkowska J, Marciniak-Czochra A, Gratchev A. Perspectives of mathematical modeling for understanding of intracellular signaling and vesicular trafficking in macrophages. Immunobiology, 2008;212(9-10):813-25

7.       Kzhyshkowska J, Gratchev A and Goerdt S. Human chitinases and chitinase-like proteins as indicators for inflammation and cancer. Biomarker Insights 2007:2 128:146

8.       Kzhyshkowska J, Gratchev A, Goerdt S. Stabilin-1, a homeostatic scavenger receptor with multiple functions. J Cell Mol Med 2006; 10(3):635-649.

9.       Dobner T, Kzhyshkowska J. Nuclear export of adenovirus RNA. Curr Top Microbiol Immunol 2001; 259:25-54.

Kzhyshkowska J, Kremmer E, Goerdt S.”GL008 is a novel human macrophage putative chemokine upregulated by Th2 cytokines and corticoids in donor-dependent manner”. PCT-Application (international). No PCT/EP2005/008646. Applicant GSF-Forschungsz. f. Umwelt u. Gesundh., GmbH.

2003-2008   Margarete von Wrangell Habilitationsprogramm, Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg (Ministry of Science, Research and Art of Baden-Württemberg) 
2006-2009 DFG, Project B12, SFB405 “Immune Tolerance and its Disturbances” 
2007-2012 DFG GRK880/2 and GRK880§, Projects 2 and 3 
2010-2013 China Scholarship Council                
In revision  DFG application in review: Novel synaptotagmin SI-Syt: function in endocytosis, secretion and vesicle motility

Prof S. Heymans, Cardiovascular Research Institute, University Hospital Maastricht, The Netherlands
Prof. B. Arnold, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg
Prof. Helene E Sage, Benaroya Research Institute, Seattle, USA
Prof. D. Hume, University of Edinburgh, UK 
Dr. K. Stacey, University of Queensland Australia
Dr. S. Brown, University of Edinburgh, UK
Prof. F. Wieland, University Biochemistry Center, University of Heidelberg
Prof. I-S Kim, Kyungpook National University, Daegu, Republic of Korea
Dr. S. Kimura, National Cancer Institute, National Institutes of Health, Bethesda, USA
Prof. Dr. Sirpa Jalkanen, Turku University and National Public Health Institute, Turku, Finland
Prof. Sedlmayr, Medical University of Graz
Dr. A. Marciniak-Czochra, Institute of Applied Mathematics, University of Heidelberg
Dr. E Kremmer, Helmholtz Zentrum München
Dr. Georg Varga, University of Münster

Makrophagen sind eine Gruppe heterogener Zellen die zuständig sind für Abwehr, Entzündung und Reparatur, aber auch für homöostatische Gewebeprozesse. In Anlehnung an das Th1/Th2 Modell der T-Zell-Immunologie hat sich in den letzten Jahren auch für die Makrophagenbiologie eine Unterteilung in zwei funktionelle Typen von Effektorzellen bewährt: proinflammatorischen, klassisch aktivierten (M1) Makrophagen (IFN-g-, LPS-stimuliert) werden anti-inflammatorisch wirkende, alternativ aktivierte (M2) Makrophagen (IL-4, IL-10, IL13-aktiviert) gegenübergestellt.  

Tumor-assoziierte Makrophagen (TAM) stellen neben anderen Zellen eine auch quantitativ bedeutende Zellpopulation im Stroma vieler Tumoren dar. Vorstufen solcher Makrophagen werden von Tumor-sezernierten Chemokinen (CCL2, CCL3, CCL4, CCL5, M-CSF, VEGF) angelockt und differenzieren ortsständig in unterschiedliche Makrophagen-Phänotypen. Die genauere Charakterisierung dieser TAMs in verschiedenen Tumoren zeigt hauptsächlich Merkmale alternativer Aktivierung (Expression von IL-10, TGF-beta, ARG1) und nur eine geringe Ausprägung des klassischen Makrophagenprofils (Sekretion von IL-12, IL-6 und TNF-alpha). Im Zuge dieser Beobachtungen wurde den TAMs, die zunächst als zytotoxischer Angriff des Immunsystems gegen den Tumor interpretiert wurden (M1 TAMs), eine ganz andere Rolle, nämlich eine Tumor-unterstützende Rolle zugeschrieben (M2 TAMs). Alternativ aktivierte M2 TAMs sind durchaus heterogen, sowohl bzgl. der an der Induktion beteiligten Zytokine, als auch bzgl. ihres molekularen Programms.  

Für die Tumor-unterstützende Wirkung nutzen M2 TAMs wesentliche Eigenschaften alternativ aktivierten-Makrophagen im Allgemeinen, wie ihre angiogenen, immunsuppressiven und reparativen Fähigkeiten. So hemmen TAMs eine effiziente anti-tumorale Immunreaktion, indem sie – gebahnt durch transkriptionelle Prozesse - IL-10, PGE2 und TGF-β produzieren. Darüber hinaus sezernieren TAMs angiogene und lymphangiogene Faktoren wie VEGF-C, VEGF, PDEGF und Thymidin Phosphorylase, treiben den „angiogeneic switch“ der Tumorzellen und führen besonders in hypoxischen Tumorarealen zu vermehrter Hämangio- und Lymphagiogenese, wodurch wiederum eine frühzeitige hämato- bzw lymphogene Metastasierung begünstigt wird. Letzlich fördern TAMs das Tumorwachstum auch direkt durch die Expression von Wachstumsfaktoren. Dazu gehören EGF, HGF, PDGF, TGF-β und bFGF. 

Während über die Charakterisierung der TAMs eines Tumors einerseits Rückschlüsse auf die Tumorprognose gezogen werden können, steht andererseits über die TAMs analog zum therapeutischen Targeting von Tumorendothelien („anti-Angiogenese“-Strategie) ein weiterer Pool von Zellen des Tumorstromas für eine indirekte, aber tumorentitätenunbhängige Tumortherapie zur Verfügung. 

Zwar sind erste Ansätze zum Targeting von TAM-Populationen als neue Strategie der Tumortherapie unternommen worden, dennoch steht die genauere Charakterisierung der TAMs und ihrer Targetstrukturen in verschiedenen Tumorarten erst am Anfang.  

Im Zentrum des Projektes dieser Arbeitsgruppe steht daher eine umfassende funktionelle und molekulare Analyse von Tumor-assoziierten Makrophagen, (TAMs) die Identifizierung und Validierung potentieller therapeutischer Targetstrukturen von TAMs und eine daraus potetiell resultierende Entwicklung einer gegen TAMs gerichteten Tumortherapie.

Für die funktionelle und molekulare Analyse von TAMs wird die TAM-Heterogenität in Abhängigkeit vom untersuchten Tumor in Rechung gestellt; hinsichtlich der Identifizierung und Validierung von TAM-Targetstrukturen werden sowohl gemeinsame TAM-Targets unterschiedlicher Tumoren als auch spezifische TAM-Targets einzelner bedeutsamer Tumorentitäten untersucht.

Unsere Arbeitsgruppe ist immer an tatkräftigen Wissenschaftlern interessiert. Sollten Sie Interesse an einer biologischen oder medizinischen Magister- oder Doktorarbeit zum Thema „Tumor Assoziierte Makrophagen“ haben, wenden Sie sich bitte an
Dr. med. Astrid Schmieder.