A01 | PASPARAKIS

A01 | Mechanisms of cell death-induced inflammation

Prof. Dr. Manolis Pasparakis

Institute for genetics - CECAD - University of Cologne

Contact: pasparakisuni-koeln.de
For more information see: Pasparakis lab

Abstract

Studies in mouse models provided evidence that cell death triggers inflammation, however the underlying mechanisms remain elusive. Using relevant genetic mouse models, this project will study the mechanisms by which different types of cell death trigger inflammation in vivo, focusing primarily on apoptosis and necroptosis. Major focus areas will be the in vivo role of specific DAMPs and their receptors as well as the mechanisms determining DAMP release via plasma membrane permeabilisation and their functional consequences in triggering cell death-induced inflammation.

Recent Publications

2025

Koerner L, Li X, Silnov E, Laurien L, Pasparakis M. RIPK1 autophosphorylation at S161 mediates cell death and inflammation. J Exp Med. 2025 Dec 1;222(12):e20250279. doi: 10.1084/jem.20250279. Epub 2025 Sep 25. PMID: 40996439; PMCID: PMC12462663.

Kaya GG, Schwarzer R, Dannappel M, Vlantis K, Göbel U, Kondylis V, Nedospasov SA, Pasparakis M. Unfolded protein response transcription factor XBP1 suppresses necroptosis-induced colitis by reinforcing the mucus barrier. Immunity. 2025 Sep 9;58(9):2208-2225.e6. doi: 10.1016/j.immuni.2025.07.023. Epub 2025 Aug 26. PMID: 40865520.

Ros U, Martinez-Osorio V, Valiente PA, Abdelwahab Y, Gojkovic M, Shalaby R, Zanna S, Saggau J, Wachsmuth L, Nemade HN, Zoeller J, Lottermoser H, Chen YG, Ibrahim M, Kelepouras K, Vasilikos L, Bedoya P, Espiritu RA, Müller S, Altmannova V, Tieleman DP, Weir J, Langer J, Adam M, Walczak H, Wong WW, Liccardi G, Mollenhauer M, Pasparakis M, Peltzer N, García-Sáez AJ. MLKL activity requires a splicing-regulated, druggable intramolecular interaction. Mol Cell. 2025 Apr 3:S1097-2765(25)00259-X. doi: 10.1016/j.molcel.2025.03.015. Epub vor dem Druck. PMID: 40209701

Project A01 Publications 2nd Funding Period 2024 - 2027

2024

Nagata M, Carvalho Schäfer Y, Wachsmuth L, Pasparakis M. A shorter splicing isoform antagonizes ZBP1 to modulate cell death and inflammatory responses. EMBO J. 2024 Sep 19. doi: 10.1038/s44318-024-00238-7. Epub ahead of print. PMID: 39300211.

Koerner L, Wachsmuth L, Kumari S, Schwarzer R, Wagner T, Jiao H, Pasparakis M. ZBP1 causes inflammation by inducing RIPK3-mediated necroptosis and RIPK1 kinase activity-independent apoptosis. Cell Death Differ. 2024 Jun 7. doi: 10.1038/s41418-024-01321-6. Epub ahead of print. PMID: 38849574.

Imai T, Lin J, Kaya G, Ju E, Kondylis V, Kelepouras K, Liccardi G, Kim C, Pasparakis M. 1,2,4. The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation. Immunity 57, 1–17, https://doi.org/10.1016/j.immuni.2024.04.016

Eren, R.O., Kaya, G.G., Schwarzer, R. and Pasparakis, M. (2024). IKKε and TBK1 prevent RIPK1 dependent and independent inflammation. Nat Commun. 15, 130. doi: 10.1038/s41467-023-44372-y.

Project A01 Publications 1st Funding Period 2020 - 2023

2023

Moschandrea, C., Kondylis, V., Evangelakos, I., Herholz, M., Schneider, F., Schmidt, C., Yang, M., Ehret, S., Heine, M., Jaeckstein, M.Y., Szczepanowska, K., Schwarzer, R., Baumann, L., Bock, T., Nikitopoulou, E., Brodesser, S., Krüger, M., Frezza, C., Heeren, J., Trifunovic, A., and Pasparakis, M. (2023). Mitochondrial dysfunction abrogates dietary lipid processing in enterocytes. Nature. 20. doi: 10.1038/s41586-023-06857-0.

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

Imai, T., Van, TM., Pasparakis, M., Polykratis, A. (2022). Smooth muscle cell specific NEMO deficiency inhibits atherosclerosis in ApoE^−/− mice. Sci Rep 12, 12538 (2022). https://doi.org/10.1038/s41598-022-16737-8

Jiao, H., Wachsmuth, L., Wolf, S., Lohmann, J., Nagata, M., Kaya, G. G., Oikonomou, N., Kondylis, V., Rogg, M., Diebold, M., Tröder, S.E., Zevnik, B., Prinz, M., Schell, C., Young, G.R., Kassiotis, G: & Pasparakis, M. (2022) ADAR1 averts fatal type I interferon induction by ZBP1. Nature (2022). https://doi.org/10.1038/s41586-022-04878-9

2021

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

Wenzel, J., Lampe, J., Müller-Fielitz, H., Schuster, R., Zille, M., Müller, K., Krohn, M., Körbelin, J., Zhang, L., Özorhan, Ü., Neve, V., Wagner, J.U.G., Bojkova, D., Shumliakivska, M., [...] Altmeppen, H.C., Pasparakis, M., Dimmeler, S., Cinatl, J., Püschel, K., Zelic, M., Ofengeim, D., Stadelmann, C., Trottein, F., Nogueiras, R., Hilgenfeld, R., Glatzel, M., Prevot, V., & Schwaninger, M. (2021) The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells. Nat Neurosci. https://doi.org/10.1038/s41593-021-00926-1

Schünke, H., Göbel, U., Dikic, I., Pasparakis, M. (2021). OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice. Nature Communications 12, Article Number: 5912 https://doi.org/10.1038/s41467-021-25945-1

Oikonomou, N., Schuijs, M.J., Chatzigiagkos, A., Androulidaki, A., Aidinis, V., Hammad, H., Lambrecht, B.N., and Pasparakis, M. (2021) Airway epithelial cell necroptosis contributes to asthma exacerbation in a mouse model of house dust mite-induced allergic inﬂammation. Mucosal Immunology https://doi.org/10.1038/s41385-021-00415-5

Kumari, S., Van, T.-M., Preukschat, D., Schuenke, H., Basic, M., Bleich, A., Klein, U., Pasparakis, M. (2021) NF-κB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation. Life Science Alliance 15 April 2021. DOI: 10.26508/lsa.202000956

2020

Laurien, L., Nagata, M., Schünke, H., Delanghe, T., Wiederstein, J., L., Kumari, S., Schwarzer, R., Corona, T., Krüger, M., Bertrand, M., J., M., Kondylis, V. & Pasparakis, M. (2020). Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation. Nat. Comm. Volume 11, Article number: 1747. https://doi.org/10.1038/s41467-020-15466-8

Schwarzer, R., Jiao, H., Wachsmuth, L., Tresch, A., Pasparakis, M. (2020). FADD and Caspase-8 Regulate Gut Homeostasis and Inflammation by Controlling MLKL- and GSDMD-Mediated Death of Intestinal Epithelial Cells. Immunity Volume 52, Pages 1-16. https://doi.org/10.1016/j.immuni.2020.04.002 For free acces please go here

Schwarzer, R., Laurien, L., Pasparakis, M. (2020). New insights into the regulation of apoptosis, necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8. Curr. Opin. Cell Biol. Volume 63, Pages 186-193. https://doi.org/10.1016/j.ceb.2020.02.004

Jiao, H., Wachsmuth, L., Kumari, S., Schwarzer, R., Lin, J., Eren, R., O., Fisher, A., Lane, R., Young, G., R., Kassiotis, G., Kaiser W., J., Pasparakis, M. (2020). Z-nucleic-acid sensing triggers ZBP1dependent necroptosis and inflammation. Nature, https://doi.org/10.1038/s41586-020-2129-8

Project related Publications

2007 - 2019

Polykratis A, Martens A, Eren RO, Shirasaki Y, Yamagichi M, Yamaguchi Y, Uemura S, Miura M, Holzmann B, Kollias G, Armaka M, van Loo G,* Pasparakis, M.* (2019) A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin binding domain. Nat. Cell Biol. 21, 731-742.

Lin, J., Kumari, S., Kim, C., Van, T.M., Wachsmuth, L., Polykratis, A., and Pasparakis, M.* (2016). RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature 540, 124-128.

Vlantis, K., Wullaert, A., Polykratis, A., Kondylis, V., Dannappel, M., Schwarzer, R., Welz, P., Corona, T., Walczak, H., Weih, F., Klein, U., Kelliher, M. and Pasparakis, M.* (2016). NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-kappaB-Dependent and -Independent Functions. Immunity 44, 553-567.

Kondylis, V., Polykratis, A., Ehlken, H., Ochoa-Callejero, L., Straub, B.K., Krishna-Subramanian, S., Van, T.M., Curth, H.M., Heise, N., Weih, F., Klein, U., Schirmacher, P., Kelliher, M. and Pasparakis, M.* (2015). NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. Cancer Cell 28, 582-598.

Dannappel, M., Vlantis, K., Kumari, S., Polykratis, A., Kim, C., Wachsmuth, L., Eftychi, C., Lin, J., Corona, T., Hermance, N., Zelic, M., Kirsch, P., Basic, M., Bleich, A., Kelliher, M. & Pasparakis, M.* (2014). RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90-94.

Ehlken, H., Krishna-Subramanian, S., Ochoa-Callejero, L., Kondylis, V., Nadi, N.E., Straub, B.K., Schirmacher, P., Walczak, H., Kollias, G., and Pasparakis, M.* (2014). Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout. Cell Death Differ 21, 1721-1732.

Kumari, S., Redouane, Y., Lopez-Mosqueda, J., Shiraishi, R., Romanowska, M., Lutzmayer, S., Kuiper, J., Martinez, C., Dikic, I.,* Pasparakis, M.,* and Ikeda, F.* (2014). Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. Elife 3.

Bonnet, M.C., Preukschat, D., Welz, P.S., van Loo, G., Ermolaeva, M.A., Bloch, W., Haase, I., and Pasparakis, M.* (2011). The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35, 572-582.

Welz, P.S., Wullaert, A., Vlantis, K., Kondylis, V., Fernandez-Majada, V., Ermolaeva, M., Kirsch, P., Sterner-Kock, A., van Loo, G., and Pasparakis, M.* (2011). FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330-334.

Nenci, A., Becker, C., Wullaert, A., Gareus, R., van Loo, G., Danese, S., Huth, M., Nikolaev, A., Neufert, C., Madison, B., Gumucio, D., Neurath, M.F., and Pasparakis, M.* (2007). Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557-561.

*Corresponding authors

UNIVERSITÄT ZU KÖLN

Sonderforschungsbereich 1403