B01 - Kashkar & Fritsch

B01 - Role of apoptotic caspases in macrophage-mediated anti-bacterial immunity

Hamid Kashkar

Institute for Molecular Immunology, CECAD
Contact: h.kashkar(at)uni-koeln.de
For more information visit: Kashkar lab

Melanie Fritsch

Institute for Molecular Immunology, CECAD
Contact: melanie.fritsch(at)uk-koeln.de
For more information visit: Kashkar lab

Abstract

Macrophages are key players in host defence, inflammation, tissue homeostasis and repair. Different modes of macrophage death including apoptosis, necroptosis and pyroptosis have been described, in particular upon interaction with bacterial pathogens. Recent observations strongly indicated that pro-apoptotic caspase activity is a versatile cellular tool that can cause different cellular outcomes by acting as a switch regulating different modes of cell death. This project will investigate the role of pro-apoptotic caspases in macrophage-mediated anti-bacterial immunity.

Recent Publications

2024

Joseph AM, Ahmed A, Goc J, Horn V, Fiedler B, Garone D, Grigg JB, Uddin J, Teng F, Fritsch M, Viver E, Sonnenberg GF, RIPK3 and caspase-8 interpret cytokine signals to regulate ILC3 survival in the gut. ScienceDirect11 August 202; doi.org/10.1016/j.mucimm.2024.08.0.

Project B01 Publications 1st Funding Period 2020 - 2023

2023

Schorn, F., Werthenbach, J.P., Hoffmann, M., Daoud, M., Stachelscheid, J., Schiffmann, L.M., Hildebrandt, X., Lyu, S.I., Peltzer, N., Quaas, A., Vucic, D., Silke, J., Pasparakis, M. and Kashkar, H. (2023) cIAPs control RIPK1 kinase activity-dependent and -independent cell death and tissue inflammation. EMBO J. doi: 10.15252/embj.2023113614

Injarabian, L., Willenborg, S., Welcker, D., Sanin, D.E., Pasparakis, M., Kashkar, H. and Eming, S.A. (2023) FADD- and RIPK3-mediated cell death ensures clearance of Ly6C^high wound macrophages from damaged tissue. J Invest Dermatol. doi: 10.1016/j.jid.2023.06.203.

2022

Maekawa, T., Kashkar, H. & Coll, N.S. Dying in self-defence: a comparative overview of immunogenic cell death signalling in animals and plants. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01060-6 (review)

Daoud, M., Broxtermann, P.N., Schorn, F., Werthenbach, J.P., Seeger, J.M., Schiffmann, L.M., Brinkmann, K., Vucic, D., Tüting, T., Mauch, C., Kulms, D., Zigrino, P., Kashkar, H. (2022) XIAP promotes melanoma growth by inducing tumour neutrophil infiltration. EMBO Reports (2022)e53608 https://doi.org/10.15252/embr.202153608

Simpson, D.S., Pang, J., Weir, A., Kong, I.Y., Fritsch, M., Rashidi, M., Cooney, J.P., Davidson, K.C., Speir, M., Djajawi, T.M., Hughes, S., Mackiewicz, L., Dayton, M., Anderton, H., Doerflinger, M., Deng, Y., Huang, A.S., Conos, S.A., Tye, H., Chow, S.H., Rahman, A., Norton, R.S., Naderer, T., Nicholson, S.E., Burgio, G., Man, S.M., Groom, J.R,. Herold, M.J., Hawkins, E.D., Lawlor, K.E., Strasser, A., Silke, J., Pellegrini, M., Kashkar, H., Feltham, R., Vince, J.E. (2022) Interferon-g primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway. Immunity 55, 1–19, March 8, 2022 https://doi.org/10.1016/j.immuni.2022.01.003

2021

Flores-Romero, H., Hohorst, L., John, M., Albert, M.-C., King, L.E., Beckmann, L., Szabo, T., Hertlein, V., Luo, X., Villunger, A., Frenzel, L.P., Kashkar, H., & Garcia-Saez, A.J. (2021) BCL-2-family protein tBID can act as a BAX-like effector of apoptosis. The EMBO Journal (2021) e108690 DOI10.15252/embj.2021108690

Theobald, S.J., Gräb, J., Fritsch, M., Suárez, I., Eisfeld, H.S., Winter, S., Koch, M., Hölscher, C., Pasparakis, M., Kashkar, H., and Rybniker, J. (2021) Gasdermin D mediates host cell death but not interleukin-1β secretion in Mycobacterium tuberculosis-infected macrophages. Cell Death Discov. 7, 327 (2021). https://doi.org/10.1038/s41420-021-00716-5

Geueke, A., Mantellato, G., Kueste, F., Schettina, P., Nelles, M., Seeger, J.M., Kashkar, H., & Niemann, C. (2021) The anti-apoptotic Bcl-2 protein regulates hair follicle stem cell function. EMBO reports e52301 https://doi.org/10.15252/embr.202052301

2020

Mayer, C.T., Nieke, J.P., Gazumyan, A., Cipolla, M., Wang, Q., Oliveira, Y.T., Ramos, V., Monette, S., Li, Q.Z., Gershwin, M.E., Kashkar, H., Nussenzweig, M.C. (2020) An apoptosis-dependent checkpoint for autoimmunity in memory B and plasma cells. Proc Natl Acad Sci U S A [Epub ahead of print] https://doi.org/10.1073/pnas.2015372117

Albert, M.C., Brinkmann, K., Pokrzywa, W., Günther, S.D., Krönke, M., Hoppe, T. & Kashkar, H. (2020). CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage. Cell Death Dis 11, 740. https://doi.org/10.1038/s41419-020-02923-x

Schiffmann, L.M., Werthenbach, J.P., Heintges-Kleinhofer, F., Seeger, J.M., Fritsch, M., Günther, S.D., Willenborg,S., Brodesser,S., Lucas, C. Jüngst, C., Albert, M.C., Schorn, F.,Witt, A., Moraes, C.T., Bruns, C.J., Pasparakis, M., Krönke, M., Eming, S.A., Coutelle, O., Kashkar, H. (2020). Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. Nat Comm. Volume 11, Article Number: 3653. https://doi.org/10.1038/s41467-020-17472-2

Günther SD, Fritsch M, Seeger JM, Schiffmann LM, Snipas SJ, Coutelle M, Kufer TA, Higgins PG, Hornung V, Bernardini ML, Höning S, Krönke M, Salvesen GS, Kashkar H. (2020) Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through lipopolysaccharide. Nat. Microbiol. 5:354–367.

Project related Publications

2014 - 2019

Fritsch M, Günther SD, Schwarzer R, Albert MC, Schorn F, Werthenbach JP, Schiffmann LM, Stair N, Stocks H, Seeger JM, Lamkanfi M, Krönke M, Pasparakis M, Kashkar H. (2019) Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 575:683-687.

Grab, J., Suarez, I., van Gumpel, E., Winter, S., Schreiber, F., Esser, A., Holscher, C., Fritsch, M., Herb, M., Schramm, M., Wachsmuth, L., Pallasch, C., Pasparakis, M., Kashkar, H., Rybniker, J. (2019). Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition. Nat Commun 10, 688.

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., Müller, R., Hornung, V. (2018). BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1beta Maturation in Macrophages. Cell Rep 25, 2354-2368 e2355.

Hösel, M., Quasdorff, M., Ringelhan, M., Kashkar, H., Debey-Pascher, S., Sprinzel, M.F., Bockmann, J.H., Arzberger, S., Webb, D., von Olshhausen, G., Weber, A., Schulze, J.L., Büning, H., Heikenwalder, M., Protzer, U. (2017) Hepatitis B virus activates signal transducer and activator of transcription 3 supporting hepatocyte survival and virus replication. Cell Mol. Gastroentrol. Hepatol. 4(3):339-363

Witt, A., Seeger, J.M., Coutelle, O., Zigrino, P., Broxtermann, P., Andree, M., Brinkmann, K., Jungst, C., Schauss, A.C., Schull, S., Wohlleber, D., Knolle, P., Krönke, M., Mauch, C., Kashkar, H. (2015). IAP antagonization promotes inflammatory destruction of vascular endothelium. EMBO Rep 16, 719-727.

Andree, M., Seeger, J.M., Schull, S., Coutelle, O., Wagner-Stippich, D., Wiegmann, K., Wunderlich, C.M., Brinkmann, K., Broxtermann, P., Witt, A., Fritsch, M., Martinelli, P., Bielig, H., Lamkemeyer, T., Rugarli, E.I., Kaufmann, T., Sterner-Koch, A., Wunderlich, F.T., Villunger, A., Martins, L.M., Krönke, M., Kufer, T.A., Utermöhlen, O., Kashkar, H. (2014). BID-dependent release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella. EMBO J 33, 2171-2187.

UNIVERSITÄT ZU KÖLN

Sonderforschungsbereich 1403