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A04 - Cellular responses to and molecular pathways of macrophage pyroptosis

Eicke Latz

Institute of Innate Immunity, University Hospital Bonn, University of Bonn

Contact: eicke.latzSpamProtectionuni-bonn.de
For more information visit: Latz Lab

 

Florian Schmidt

Institute of Innate Immunity, University Hospital Bonn, University of Bonn

Contact: fschmidtSpamProtectionuni-bonn.de
For more information visit: Schmidt Lab

Abstract

The identity of most pyroptosis-dependent proinflammatory and potentially regulatory factors and their effects on surrounding cells is poorly understood. The project will study the molecular details and functional consequences of pyroptosis-dependent secreted factors and the mechanisms and kinetics of pore formation by gasdermins. These studies aim to unravel novel pathways involved in chronic tissue damage and inflammatory diseases involving pyroptosis.

Project related Publications

Christ, A., Günther, P., Lauterbach, M.A.R., Duewell, P., Biswas, D., Pelka, K., Scholz, C.J., Oosting, M., Haendler, K., Baßler, K., Klee, K., Schulte-Schrepping, J., Ulas, T., Moorlag, S.J.C.F.M., Kumar, V., Park, M.H., Joosten, L.A.B., Groh, L.A., Riksen, N.P., Espevik, T., Schlitzer, A., Li, Y., Fitzgerald, M.L., Netea, M.G., Schultze, J.L., and Latz, E. (2018). West-ern diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162-175.

Venegas, C.M., Kumar, S., Franklin, B.S., Dierkes, T., Brinkschulte, R., Tejera, D., Vieira-Saecker, A., Schwartz, S., Santarelli, F., Kummer, M.P., Griep, A., Gelpi, E., Beilharz, M., Riedel, D., Golenbock, D.T., Geyer, M., Walter, J., Latz, E., and Heneka M.T. (2017). In-flammasome-triggered ASC specks cross-seed β-amyloid deposition in Alzheimer’s disease. Nature 552, 355–361.

Bertheloot, D., Naumovski, A.L., Langhoff, P., Horvath, G.L., Jin, T., Xiao, T.S., Garbi, N., Agrawal, S., Kolbeck, R., and Latz, E. (2016). RAGE Enhances TLR Responses through Binding and Internalization of RNA. J. Immunol. 197, 4118-4126.

Franklin, B.S., Bossaller, L., De Nardo, D., Ratter, J.M., Stutz, A., Engels, G., Brenker, C., Nordhoff, M., Mirandola, S.R., Al-Amoudi, A., Mangan, M.S., Zimmer, S., Monks, B.G., Fricke, M., Schmidt, R.E., Espevik, T., Jones, B., Jarnicki, A.G., Hansbro, P.M., Busto, P., Marshak-Rothstein, A., Hornemann, S., Aguzzi, A., Kastenmüller, W., and Latz, E. (2014). The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat. Immunol.15, 727-737.

De Nardo, D., Labzin, L.I., Kono, H., Seki, R., Schmidt, S.V., Beyer, M., Xu, D., Zimmer, S., Lahrmann, C., Schilberg, F.A., Vogelhuber, J., Kraut, M., Ulas, T., Kerksiek, A., Krebs, W., Bode, N., Grebe, A., Fitzgerald, M.L., Hernandez, N.J., Williams, B., Knolle, P.A., Kneiling, M., Rocken, M., Lutjohann, D., Wright, S.D., Schultze, J.L., and Latz, E. (2014). HDL mediates anti-inflammatory transcriptional reprogramming of macrophages via ATF3. Nat. Immunol. 15, 152-160.

Heneka, M.T.*, Kummer, M.P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., Griep, A., Axt, D., Remus, A., Tzeng, T.C., Gelpi, E., Halle, A., Korte, M., Latz, E.*, and Golenbock, D.T.* (2013). NLRP3 is activated in Alzheimer's disease and contributes to pathol-ogy in APP/PS1 mice. Nature 493, 674-678. *equal contribution

Sirois, C.M., Jin, T., Miller, A.L., Bertheloot, D., Nakamura, H., Horvath, G.L., Mian, A., Jiang, J., Schrum, J., Bossaller, L., Pelka, K., Garbi, N., Brewah, Y., Tian, J., Chang, C., Chow-dhury, P.S., Sims, G.P., Kolbeck, R., Coyle, A.J., Humbles, A.A., Xiao, T.S., and Latz, E. (2013). RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. J. Exp. Med. 210, 2447-2463.

Duewell, P., Kono, H., Rayner, K.J., Sirois, C.M., Vladimer, G., Bauernfeind, F.G., Abela, G.S., Franchi, L., Nunez, G., Schnurr, M., Espevik, T., Lien, E., Fitzgerald, K.A., Rock, K.L., Moore, K.J., Wright, S.D., Hornung, V., and Latz, E. (2010). NLRP3 inflammasomes are re-quired for atherogenesis and activated by cholesterol crystals. Nature 464, 1357-1361.

Schmidt, F.I., Hanke, L., Morin, B., Brewer, R., Brusic, V., Whelan, S.P., Ploegh, H.L. (2016). Phenotypic lentivirus screens to identify functional single domain antibodies. Nat. Microbiol. 1, 16080.

Schmidt, F.I.*, Lu, A.*, Chen, J.W., Ruan, J., Tang, C., Wu, H., Ploegh, H.L. (2016). A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly. J Exp Med. 213, 771-790. *equal contribution