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The Role of Integrins and Cytoskeletal Forces in Interstitial Leukocyte Migration

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The Role of Integrins and Cytoskeletal Forces in Interstitial Leukocyte Migration Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München The role of integrins and cytoskeletal forces in interstitial leukocyte migration Tim Lämmermann aus Fürth 2009 Erklärung Diese Dissertation wurde im Sinne von § 13 Abs. 3 der Promotionsordnung vom 29. Januar 1998 von Herrn Prof. Dr. Reinhard Fässler betreut. Ehrenwörtliche Versicherung Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet. München, am 20.4.2009 Tim Lämmermann Dissertation eingereicht am 21.4.2009 1. Gutachter: Prof. Dr. Reinhard Fässler 2. Gutachter: Prof. Dr. Markus Sperandio Mündliche Prüfung am 28.5.2009 Table of contents 1 Table of contents 1 TABLE OF CONTENTS .............................................................................................................................I 2 LIST OF PUBLICATIONS ....................................................................................................................... II 3 ABBREVIATIONS....................................................................................................................................III 4 SUMMARY................................................................................................................................................IV 5 INTRODUCTION ....................................................................................................................................... 1 5.1 LEUKOCYTE MIGRATION IN GENERAL ................................................................................................... 1 5.1.1 Principle trafficking processes........................................................................................................ 1 5.1.2 Trafficking molecules ...................................................................................................................... 2 5.2 INTEGRINS ON LEUKOCYTES ................................................................................................................. 4 5.2.1 Integrin structure and functions...................................................................................................... 4 5.2.2 Integrin activation in leukocytes ..................................................................................................... 6 5.2.3 Functions of integrins in leukocyte migration................................................................................. 8 5.2.3.1 Extravasation......................................................................................................................................... 8 5.2.3.2 Interstitial migration............................................................................................................................ 11 5.3 AMOEBOID MIGRATION OF LEUKOCYTES ............................................................................................ 12 5.3.1 Amoeboid migration..................................................................................................................... 12 5.3.2 Cellular forces in amoeboid migration ......................................................................................... 13 5.3.2.1 Balancing adhesion and contraction .................................................................................................... 15 5.3.2.2 Balancing contraction and polymer network expansion ...................................................................... 17 5.4 DENDRITIC CELL MIGRATION ..................................................................................................................... 18 5.4.1 Dendritic cells in general.............................................................................................................. 18 5.4.2 Dendritic cell trafficking from the skin to the lymph node ............................................................ 19 5.4.2.1 Mobilization and principle guidance cues ........................................................................................... 19 5.4.2.2 Dendritic cell trafficking in the skin.................................................................................................... 20 5.4.2.3 Dendritic cell trafficking into the lymphatic vessel............................................................................. 22 5.4.2.4 Dendritic cell trafficking within the lymph node................................................................................. 24 5.4.3 Cytoskeletal regulation of dendritic cell migration....................................................................... 26 6 AIM OF THE THESIS.............................................................................................................................. 28 7 BRIEF SUMMARIES OF THE PUBLICATIONS................................................................................ 29 7.1 SUMMARY PAPER I ............................................................................................................................. 29 7.2 SUMMARY PAPER II (REVIEW)............................................................................................................ 29 7.3 SUMMARY PAPER III (REVIEW) .......................................................................................................... 30 7.4 SUMMARY PAPER IV (REVIEW) .......................................................................................................... 30 7.5 SUMMARY PAPER V............................................................................................................................ 31 7.6 SUMMARY PAPER VI .......................................................................................................................... 32 7.7 SUMMARY PAPER VII ......................................................................................................................... 32 8 ACKNOWLEDGEMENTS ...................................................................................................................... 33 9 CURRICULUM VITAE ........................................................................................................................... 34 10 REFERENCES.......................................................................................................................................... 35 11 SUPPLEMENTS........................................................................................................................................ 45 I List of publications 2 List of Publications The thesis is based on the following publications which are referred to in the text by their Roman numerals (I–VII): I. Haiyan Chu, Ingo Thievessen, Michael Sixt, Tim Lämmermann, Ari Waisman, Attila Braun, Angelika A. Noegel, Reinhard Fässler. γ-Parvin is dispensable for hematopoiesis, leukocyte trafficking, and T-cell-dependent antibody response. Molecular and Cellular Biology. 2006 Mar; 26(5):1817-25. II. Michael Sixt, Martina Bauer, Tim Lämmermann, Reinhard Fässler. β1 integrins: zip codes and signaling relay for blood cells. Current Opinion in Cell Biology. 2006 Oct; 18(5):482-90. Review. III. Zerina Lokmic*, Tim Lämmermann*, Michael Sixt, Susanna Cardell, Rupert Hallmann, Lydia Sorokin. The extracellular matrix of the spleen as a potential organizer of immune cell compartments. Seminars in Immunology. 2008 Feb; 20(1):4-13. Review. * equally contributing first authors. IV. Tim Lämmermann, Michael Sixt. The microanatomy of T-cell responses. Immunological Reviews. 2008 Feb; 221:26-43. Review. V. Tim Lämmermann, Bernhard L. Bader, Susan J. Monkley, Tim Worbs, Roland Wedlich-Söldner, Karin Hirsch, Markus Keller, Reinhold Förster, David R. Critchley, Reinhard Fässler, Michael Sixt. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature. 2008 May 1; 453(7191):51-5. VI. Kai Kessenbrock, Leopold Fröhlich, Michael Sixt, Tim Lämmermann, Andrew Bateman, Azzaq Belaaouaj, Johannes Ring, Markus Ollert, Reinhard Fässler, Dieter E. Jenne. Proteinase 3 and neutrophil elastase enhance inflammation by inactivating anti- inflammatory progranulin. Journal of Clinical Investigations. 2008 Jul; 118(7):2438-47. VII. Tim Lämmermann , Jörg Renkawitz, Xunwei Wu, Karin Hirsch, Cord Brakebusch, Michael Sixt. Cdc42-dependent leading edge coordination is essential for interstitial dendritic cell migration. Blood. 2009 Jun 4; 113(23):5703-10. Epub 2009 Feb 3. Reprints were made with permission from the publisher. II Abbreviations 3 Abbreviations 2D two-dimensional LFA-1 lymphocyte function-associated 3D three-dimensional antigen 1 APC antigen-presenting cell LN lymph node Arp2/3 actin-related protein 2/3 Mac-1 macrophage antigen 1 BM basement membrane MAdCAM-1 mucosal vascular addressin cell CalDAG Ca2+ and diacylglycerol-regulated adhesion molecule 1 guanine nucleotide exchange factor MHC major histocompatibility complex CCL CC-chemokine ligand MMP matrix metalloproteinase CCR CC-chemokine receptor MSP major sperm protein CD cluster of differentiation PECAM-1 platelet/endothelial cell adhesion Cdc42 cell division cycle 42 molecule 1 CLEVER-1 common lymphatic endothelial and PGC primordial germ cell vascular endothelial receptor 1 PI3K phosphoinositide-3 kinase CXCL CXC-chemokine ligand PIP3 phosphoinositol-3,4,5-triphosphate CXCR CXC-chemokine receptor PNAd peripheral lymph node addressin DC dendritic cell PPs Peyer’s patches dDC dermal dendritic cell PSGL-1 P-selectin glycoprotein ligand 1 ECM extracellular matrix PTB phospho-tyrosine binding ESAM endothelial cell-selective adhesion Rac ras-related C3 botulinum toxin
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