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Project 28
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Project 28

Wolfgang Kastenmüller

In vivo visualization of inflammasome activation in the context of acute bacterial infections

Institute of Molecular Medicine and Experimental Immunology, University Hospital of Bonn

Brief description in German
Das Immunsystem besteht aus einem dynamischen Organsystem, deren einzelne zelluläre Bestandteile sich ständig in Bewegung befinden - auf der Suche nach eindringenden Pathogenen. Dabei spielen die Rezeptoren des angeborenen Immunsystems eine besondere Rolle, da sie Infektionen schnell und spezifisch erkennen können. Die daraus resultierenden Signale wie Zytokine führen zur Rekrutierung von weißen Blutkörperchen, die dann die Infektion bekämpfen und eliminieren.

In den letzten Jahren sind die sogenannten NOD-like Rezeptoren als neue Repräsentanten des angeborenen Immunsystems in den Vordergrund getreten. Ihre Aktivierung führt zur Sekretion von IL1 und IL18, welche unter anderem Lymphozyten aktivieren.

In unserem Projekt gehen wir der Frage nach, mit welcher Dynamik das angeborene Immunsystem auf eine akute bakterielle Infektion reagiert. Dazu verwenden wir die intravitale 2-Photonen Mikroskopie, die es uns erlaubt, die Ausbreitung einer Infektion in vivo zu visualisieren und gleichzeitig zu beobachten, wie das Immunsystem darauf antwortet.

 

27-10-13 4h Specs CFP CD31 647, Lyve-PE, LysMGFP 5th_001_neu.jpg

Whole mount of skin showing neutrophils (green), blood vessels (red), ASC specks (white) and keratinocytes (blue), 4h after injection of purified ASC aggregates. by Wolfgang Kastenmüller

Summary
The immune system represents a highly flexible and dynamic organ system that has primarily evolved to fight off invading pathogens. In principle this system can be divided into two functionally connected parts - the innate and the adaptive immune system. NOD-like receptors can activate a larger multiprotein complex, the so-called inflammasome, which in turn leads to activation and secretion of inflammatory cytokines like IL-1 and IL-18.

We have recently identified that inflammasome signals in the context of bacterial infections link the innate and adaptive immune system. Specifically IL-18 activates memory CD8+ T cells to produce IFNg in a non-cognate manner.

Our static imaging analyses of this process, using frozen tissue sections, point to a highly dynamic and organized order of events. Therefore our central hypothesis is that the propagation of inflammasome activation in the tissue is a highly dynamic process involving resident and recruited myeloid cells.

In this work we aim to unravel the in vivo dynamics of inflammasome activation and the resolution of inflammation in the context of acute bacterial infections in the skin and lymph nodes. To this end, we will apply a novel reporter mouse line (ASC-Cerulean) to investigate when and where inflammasome activation takes place in relation to infectious foci using 2-photon intravital microscopy and multicolour histocytometry.

Our investigation will reveal in which cells the inflammasome is activated in a dynamic fashion and which cells help to dampen the propagation of innate immunes signals in the tissue. This study will provide novel insights into pathogen defense by the immune system and will uncover basic principles of the dynamics of inflammasome activation in living animals.

List of relevant publications
Wolfgang Kastenmüller has moved his laboratory to Germany (University of Bonn) in January 2012. Thus, the listed publications that are relevant to this project have not been funded by this CRC 670.

Peer reviewed publications:

Eickhoff S, Brewitz A, Gerner MY, Klauschen F, Komander K, Hemmi H, Garbi N, Kaisho T, Germain RN, Kastenmüller W. 2015. Robust Anti-viral Immunity Requires Multiple Distinct T Cell-Dendritic Cell Interactions. Cell 162(6):1322-37

Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A, Engels G, Brenker C, Nordhoff M, Mirandola SR, Al-Amoudi A, Mangan MS, Zimmer S, Monks BG, Fricke M, Schmidt RE, Espevik T, Jones B, Jarnicki AG, Hansbro PM, Busto P, Marshak-Rothstein A, Hornemann S, Aguzzi A, Kastenmuller W, Latz E. 2014. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat Immunol 15: 727-37

Kastenmuller W, Brandes M, Wang Z, Herz J, Egen JG, Germain RN. 2013. Peripheral prepositioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node. Immunity 38: 502-13

Kastenmuller W, Torabi-Parizi P, Subramanian N, Lammermann T, Germain RN. 2012. A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread. Cell 150: 1235-48

Gerner MY, Kastenmuller W, Ifrim I, Kabat J, Germain RN. 2012. Histo-cytometry: a method for highly multiplex quantitative tissue imaging analysis applied to dendritic cell subset microanatomy in lymph nodes. Immunity 37: 364-76

Qi H, Kastenmuller W, Germain RN. 2014. Spatiotemporal basis of innate and adaptive immunity in secondary lymphoid tissue. Annu Rev Cell Dev Biol 30: 141-67