A03 - Hornung

A03 - Identification of molecules and key pathways that drive necroptosis-dependent inflammation

Veit Hornung

Gene Center Munich, Department for Biochemistry, Ludwig-Maximilians-University Munich
Contact: hornung(at)genzentrum.lmu.de
For more information visit: Hornung lab

Abstract

Unlike apoptosis, necroptosis results in the release of cytosolic contents that are believed to induce inflammation. Using a well-established in vitro model of human cells, this project aims to characterise necroptosis-driven inflammation in vitro and to identify necroptosis-dependent DAMP or alarmin molecules. By systematically perturbing all known PRR- and cytokine receptor-dependent signalling cascades within bystander cells this project will additionally characterise the dominant sensing modalities in this setting. These efforts will provide novel mechanistic insights into how necroptosis triggers inflammation.

Recent Publications

2022

Pinci, F., Gaidt, M.M., Jung, C., Nagl, D., Kuut, G., Hornung, V. (2022) Tumor necrosis factor is a necroptosis-associated alarmin. Front. Immunol. 13:1074440. doi: 10.3389/fimmu.2022.1074440

Schmacke, N.A., O'Duill, F., Gaidt, M.M., Szymanska, I., Kamper, J.M., Schmid-Burgk, J.L., Mädler, S.C., Mackens-Kiani, T., Kozaki, T., Chauhan, D., Nagl, D., Stafford, C.A., Harz, H., Fröhlich, A.L.. Pinci, F., Ginhoux, F.L., Beckmann, R., Mann, M., Leonhardt, H., Hornung, V. (2022) IKKβ primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network. Immunity 2022 Nov 9;S1074-7613(22)00562-3. doi: 10.1016/j.immuni.2022.10.021.

Stafford, C.A., Gassauer, A.-M., de Oliveira Mann, C.C., Tanzer, M.C., Fessler, E., Wefers, B., Nagl, D., Kuut, G., Sulek, K., Vasilopoulou, C., Schwojer, S.J., Wiest, A., Pfautsch, M.K., Wurst, W., Yabal, M., Fröhlich, T., Mann, M., Gisch, N., Jae, L.T., & Hornung, V. Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. Nature 609, 590–596 (2022). https://doi.org/10.1038/s41586-022-05125-x

2021

Bauernfried. S., & Hornung, V. (2021) DPP9 restrains NLRP1 activation. Nat Struct Mol Biol. https://doi.org/10.1038/s41594-021-00580-y

2020

Pinci, F., Gaidt, M. M., Jung,C., Kuut, G., Jackson, M. A., Bauernfried, S., and Hornung, V. (2020) C-tag TNF: a reporter system to study TNF shedding. Journal of Biological Chemistry Vol 295, Issue 52. DOI 10.1074/jbc.RA120.015248

Project related Publications

2008 - 2019

Chauhan, D., Bartok, E., Gaidt, M.M., Bock, F.J., Herrmann, J., Seeger, J.M., Broz, P., Beckmann, R., Kashkar, H., Tait, S.W.G., ... and Hornung, V. (2018). BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1beta Maturation in Macrophages. Cell Rep 25, 2354-2368 e2355.

Gaidt, M.M., Ebert, T.S., Chauhan, D., Ramshorn, K., Pinci, F., Zuber, S., O'Duill, F., Schmid-Burgk, J.L., Hoss, F., Buhmann, R., ... and Hornung, V. (2017). The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3. Cell 171, 1110-1124 e1118.

Gaidt, M.M., Ebert, T.S., Chauhan, D., Schmidt, T., Schmid-Burgk, J.L., Rapino, F., Robertson, A.A., Cooper, M.A., Graf, T., and Hornung, V. (2016). Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity 44, 833-846.

Gaidt, M.M., Rapino, F., Graf, T., and Hornung, V. (2018). Modeling Primary Human Monocytes with the Trans-Differentiation Cell Line BLaER1. Methods in molecular biology (Clifton, NJ) 1714, 57-66.

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

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

Lehle, A.S., Farin, H.F., Marquardt, B., Michels, B.E., Magg, T., Li, Y., Liu, Y., Ghalandary, M., Lammens, K., Hollizeck, S., ... Hornung, V., et al. (2019). Intestinal Inflammation and Dysregulated Immunity in Patients With Inherited Caspase-8 Deficiency. Gastroenterology 156, 275-278.

Li, Y., Fuhrer, M., Bahrami, E., Socha, P., Klaudel-Dreszler, M., Bouzidi, A., Liu, Y., Lehle, A.S., Magg, T., Hollizeck, S., ... Hornung, V., et al. (2019). Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proc Natl Acad Sci U S A 116, 970-975.

Paludan, S.R., Reinert, L.S., and Hornung, V. (2019). DNA-stimulated cell death: implications for host defence, inflammatory diseases and cancer. Nat Rev Immunol 19, 141-153.

van den Boorn, J.G., Jakobs, C., Hagen, C., Renn, M., Luiten, R.M., Melief, C.J., Tuting, T., Garbi, N., Hartmann, G., and Hornung, V. (2016). Inflammasome-Dependent Induction of Adaptive NK Cell Memory. Immunity 44, 1406-1421.

Universität zu Köln

Sonderforschungsbereich 1403