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Project 22
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Project 22

Eicke Latz

Molecular mechanisms of the NLRP3 inflammasome activation

Institute for Innate Immunity, University of Bonn

Publications

Brief description in German
Inflammation ist Folge einer koordinierten Immunantwort nach Infektion oder Gewebstrauma. Die Zellen des angeborenen Immunsystems haben eine Vielzahl von Rezeptoren, die Fremdsubstanzen von Pathogenen oder veränderte Eigensubstanzen erkennen.

Eine Aktivierung von Zellen des angeborenen Immunsystem ist essentiell für eine effektive Infektionsabwehr. Das NLRP3 Inflammasom erkennt das Eindringen von Mikroben in Zellen und NLRP3 kann zusätzlich von kristallinen oder aggregierten Substanzen aktiviert werden. Nach NLRP3 Aktivierung kommt es zur Ausbildung eines Inflammasom-Signalkomplexes der aus helikalen Fibrillen des Inflammasom-Adapters ASC und Caspase-1 besteht.

Unsere Versuche haben gezeigt, dass der Inflammasom-Signalkomplexes nach Altivierung der Zelle Zugang in den extrazellulären Raum hat. In diesem Teilprojekt untersuchen wir, welche Funktion extrazelluläre Inflammasome bei der Entstehung von entzündlichen Gewebsreaktionen haben und wie man diese therapeutisch beeinflussen kann.

Summary
The innate immune system has evolved signaling receptors, which detect microbes and respond to sterile danger signals. Many microbes, their toxins as well as sterile danger signals can activate intracellular signaling platforms, termed the inflammasomes.

Upon activation, the inflammasome sensor proteins bind to the adapter protein ASC, which rapidly forms a large protein ‘speck’ leading to the recruitment of pro-caspase-1 and its autocatalytic activation. Active caspase-1 subsequently proteolytically activates IL-1β family cytokines (IL-1β and IL-18) and initiates a special type of cell death, termed pyroptosis.

Up until now, it has been assumed that these mechanisms operate exclusively intracellularly. Surprisingly, we have discovered that shortly after inflammasome activation ASC specks are released into the extracellular space, along with a large quantity of pro-caspase-1 and pro-IL-1β.

Here, ASC specks can amplify inflammatory responses by further activating pro-caspase-1 and processing of pro-IL-1β cytokines to the mature cytokines. Moreover, we found that immune cells phagoctose extracellular ASC specks, which in turn promotes new NLRP3 inflammasome activation.

Our central hypothesis is that ASC specks are released from activated immune cells and act as danger signals by activating pro-caspase-1 and IL-1β cytokines in the extracellular space. In addition, we propose that ASC specks become internalized by neighboring macrophages and potentially other cells, where they promote priming and further inflammasome activation. Extracellular ASC specks can thereby amplify the local inflammatory response.

Our goals are to define and molecularly decipher the extracellular inflammatory functions of ASC specks, to delineate the inflammatory activity of ASC specks in various tissues and to develop monoclonal blocking antibodies that can interfere with exaggerated inflammatory responses mediated by extracellular ASC specks.

We plan to test the activity of anti-ASC monoclonal antibodies in preclinical models of inflammasome-driven inflammation. These studies will reveal novel means by which signaling platforms can propagate inflammatory responses in the extracellular space. Additionally, we have identified a novel target for the treatment of inflammatory conditions associated with inflammasome activation, and we will provide proof-of-principle studies for therapeutic antibodies in preclinical models of inflammation.

List of publication resulting from the project

Peer-reviewed publications:
Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KH, Masters SL, Schroder K, Cooper MA, O'Neill LA. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015 Feb 16.

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, Kastenmüller W & Eicke Latz. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat Immunol, 2014, Aug;15(8):727-37

Hett EC, Slater LH, Mark KG, Kawate T, Monks BG, Stutz A, Latz E, Hung DT. Chemical genetics reveals a kinase-independent role for protein kinase R in pyroptosis. Nat Chem Biol. 2013 Jun;9(6):398-405.

List of further relevant publications
Eicke Latz has moved his laboratory to Germany (University of Bonn) in September 2009. Thus, the below listed publications that are relevant to this project have not been funded by this CRC 670 and only the funding sources from the USA are therefore acknowledged.

Peer reviewed publications:
Bauernfeind, F. G., Horvath, G., Stutz, A., Alnemri, E. S., MacDonald, K., Speert, D., Fernandes-Alnemri, T., Wu, J., Monks, B. G., Fitzgerald, K. A., Hornung, V. & Latz, E. 2009 Cutting edge: NF-kappaB activating patternrecognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 183:787-791

Hornung, V., Ablasser, A., Charrel-Dennis, M., Bauernfeind, F., Horvath, G., Caffrey, D. R., Latz, E*. & Fitzgerald, K.A.* 2009 AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC Nature. 458:514-518 * equal contribution

Horvath, G., Young, S. & Latz, E. 2009 Toll-like receptor interactions imaged by FRET microscopy and GFP fragment reconstitution. Methods Mol Biol. 517:33-54

Hornung, V., Bauernfeind, F., Halle, A., Samstad, E. O., Kono, H., Rock, K. L., Fitzgerald, K. A. & Latz, E. 2008 Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 9:847-856

Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, K. J. & Golenbock, D. T. 2008 The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 9:857-865

Latz, E., Verma, A., Visintin, A., Gong, M., Sirois, C. M., Klein, D. C., Monks, B. G., McKnight, C. J., Lamphier, M. S., Duprex, W. P., Espevik, T. & Golenbock, D. T. 2007Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol. 8:772-779

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