Center for Molecular Medicine Cologne

Annibaldi, Alessandro - JRG 12

Understanding the role of cell death in health and disease

We are focussed on the role of cell death in health and disease. In particular, we investigate the molecular mechanisms regulating different forms of cell death (e.g. apoptosis and necroptosis) and how cell death contributes to inflammatory programs, activated following pathogenic infection or tissue damage, as well as to tumorigenesis. Understanding the complex relationship between cell death and inflammation will help to improve the current treatments of chronic inflammatory diseases and cancer.

Introduction 

Programmed cell death is a fundamental biological process that ensures tissue development and homeostasis. However, when deregulated, cell death can induce inflammation. Genetic studies conducted in mice demonstrated that aberrant cell death is a causative factor for chronic inflammatory syndromes.
In the past few years it became clear that the cell death processes causing different autoinflammatory diseases are mediated by a serine/threonine kinase called RIPK1. Indeed, pharmacological inhibition of RIPK1 has been showed to block cell death and ameliorate inflammatory conditions such as psoriasis and inflammatory bowel disease.
It has also been shown that RIPK1-mediated cell death of cancer cells has the potential to alert and activate the immune system to mount an anti-tumour immune response. Therefore, while inhibition of RIPK1 activity appeared to be beneficial in auotinflammatory diseases, boosting its cytotoxic potential might be useful in conditions where the activation of the immune system against cancer cells is the desired outcome.

Cell death regulation in innate immunity pathways

One of our focuses is on how cell death is regulated downstream of different innate immune receptors, such as TNFR1. Once activated by TNF, TNFR1 initiates a cascade of events that trigger the activation of NF-kappaB and MAPKs, leading to the expression of pro-survival and pro-inflammatory genes (Figure 1). However, under certain circumstances, TNFR1 activation can also induce cell death in the form of apoptosis or necroptosis. Apoptosis is mediated by the kinase activity of RIPK1 and the proteolytic activity of Caspase-8, necroptosis is mediated by the kinase activity of RIPK1 and RIPK3 and the pseudokinase MLKL (Figure 1). The main goal of our work is to characterise novel mechanisms determining whether TNF stimulation induces the expression of pro-inflammatory genes or cell death and to understand the impact of these two different outcomes on tissue plasticity.
Characterizing how the life and death decision is made downstream of TNFR1 will provide a better understanding of how the immune responses are regulated followed pathogen infection or tissue injury.

Figure 1
TNF signaling pathway

Immunogenic cell death in cancer treatment

Apoptosis and necroptosis are the best understood forms of programmed cell death. It was generally thought that apoptosis is immunologically silent, since dying cells maintain plasma membrane integrity. In contrast, necroptosis is an immunogenic form of cell death as a consequence of plasma membrane disruption and spillage of existing immune-stimulatory cellular factors referred to as constitutive Damage Associated Molecular Patterns (cDAMPs). This traditional viewpoint has recently been challenged. It becomes increasingly clear that the type of cell death per se (apoptosis vs. necroptosis or other forms of programmed cell death) does not determine whether dying cells trigger effector T cell (CD8+)-mediated immune responses. CD8+T cell activation indeed requires not only malignant cell death as source of antigens, but also the active production and release of immune-stimulatory factors, called inducible DAMPs (iDAMPs) by dying cells. This ensures robust T cell cross priming and activation against malignant cells (Figure 2).

A recent study indicated RIPK1 can induce immunogenic cell death in malignant cells, regardless of the type of cell death delivered (apoptosis or necroptosis) but based on the ability of RIPK1 to activate an inflammatory program in dying cells. The mechanisms regulating RIPK1 activity have been extensively characterised in pathophysiological settings. However, the signals upstream and downstream of RIPK1 that determine its ability to induce immunogenic cell death in malignant cells are unknown. The characterisation of such signals might help the development of novel strategies to maximise the activation of the immune system against cancer cells and improve current immunotherapy.

Perspectives

It is widely accepted that cell death does not only regulate organism development and the elimination of unwanted cells, but it also actively participates to tissue repair programs. Such programs are activated following damage or infection and are also often hijacked by cancer cells to fuel their own expansion.  Characterising the mechanisms by which cell death is regulated and the role of cell death in tissue repair and adaptation will help the understanding of the processes underlying autoinflammatory diseases and tumorigenesis. Equally, the characterisation of how cell death can be exploited to activate anti-tumour immune responses might ultimately help to improve current anti-cancer therapies.

Lab Website

For further information please check here the Annibaldi Laboratory For Cell Death, Inflamation and Immunity's webpage.

Figure 2
Immunogenic cell death
  1. Ruiz, E. J., Diefenbacher, M. E., Nelson, J. K., Sancho, R., Charaborty, a., Moreno, P. Annibaldi, A. et al. (2019), J Exp Med216, 450-465.
  2. Liccardi G, Ramos Garcia L, Tenev T, Annibaldi A, et al. (2019) RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation. Mol Cell73, 413-428.
  3. Annibaldi A., Meier, P. (2018).  Ripk1 and haemato-poiesis: a case for LUBAC and Ripk3. Cell Death Differ25, 1361-1363.
  4. Feltham R., Jamal K., Tenev T., Liccardi G., Jaco I., Monteiro Domingues C., Morris O., Wicky John S., Annibaldi A., Widya M., et al. (2018) Mind bomb regulates cell death during TNF signalling by suppressing RIPK1’s cytotoxic potential. Cell Rep2, 470-484.
  5. #Annibaldi A., Wicky John S., Vanden Berghe T., et al. (2018) Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2. Mol Cell69, 566-580, #: Corresponding author.
  6. Annibaldi A., Meier, P. (2017). Checkpoints in TNF-Induced Cell Death: Implications in Inflammation and Cancer. Trends Mol Med. Dec 4, S1471-4914(17)30202-2
  7. Jaco I., *Annibaldi A., Lalaoui N., et al. (2017) MK2 phosphorylates RIPK1 to prevent TNF induced cell death. Mol Cell66, 698-710. *: Joint authorship
  • Peltzer N, and Annibaldi A (2022). Cell Death-Related Ubiquitin Modifications in Inflammatory Syndromes: From Mice to Men. Biomedicines10. doi:10.3390/biomedicines10061436.
  • Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance. Garcia LR, Tenev T, Newman R, Haich RO, Liccardi G, John SW, Annibaldi A, Yu L, Pardo M, Young SN, Fitzgibbon C, Fernando W, Guppy N, Kim H, Liang LY, Lucet IS, Kueh A, Roxanis I, Gazinska P, Sims M, Smyth T, Ward G, Bertin J, Beal AM, Geddes B, Choudhary JS, Murphy JM, Aurelia Ball K, Upton JW, Meier P. Nat Commun. 2021 Jun 7;12(1):3364. doi: 10.1038/s41467-021-23474-5. PMID: 34099649
  • Chemotherapy Induces Tumor-Associated Macrophages that Aid Adaptive Immune Responses in Ovarian Cancer. Heath O, Berlato C, Maniati E, Lakhani A, Pegrum C, Kotantaki P, Elorbany S, Böhm S, Barry ST, Annibaldi A, Barton DP, Balkwill FR. Cancer Immunol Res. 2021 Jun;9(6):665-681. doi: 10.1158/2326-6066.CIR-20-0968. Epub 2021 Apr 10. PMID: 33839687
  • Annibaldi A, and Walczak H (2020). Death Receptors and Their Ligands in Inflammatory Disease and Cancer. Cold Spring Harbor perspectives in biology 10.1101/cshperspect.a036384.
  • RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation. Liccardi G, Ramos Garcia L, Tenev T, Annibaldi A, Legrand AJ, Robertson D, Feltham R, Anderton H, Darding M, Peltzer N, Dannappel M, Schünke H, Fava LL, Haschka MD, Glatter T, Nesvizhskii A, Schmidt A, Harris PA, Bertin J, Gough PJ, Villunger A, Silke J, Pasparakis M, Bianchi K, Meier P. Mol Cell. 2019 Feb 7;73(3):413-428.e7. doi: 10.1016/j.molcel.2018.11.010. Epub 2018 Dec 28. PMID: 30598363
  • LUBAC determines chemotherapy resistance in squamous cell lung cancer. Ruiz EJ, Diefenbacher ME, Nelson JK, Sancho R, Pucci F, Chakraborty A, Moreno P, Annibaldi A, Liccardi G, Encheva V, Mitter R, Rosenfeldt M, Snijders AP, Meier P, Calzado MA, Behrens A. J Exp Med. 2019 Feb 4;216(2):450-465. doi: 10.1084/jem.20180742. Epub 2019 Jan 14. PMID: 30642944
  • Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2. Annibaldi A, Wicky John S, Vanden Berghe T, Swatek KN, Ruan J, Liccardi G, Bianchi K, Elliott PR, Choi SM, Van Coillie S, Bertin J, Wu H, Komander D, Vandenabeele P, Silke J, Meier P. Mol Cell. 2018 Feb 15;69(4):566-580.e5. doi: 10.1016/j.molcel.2018.01.027. PMID: 29452637
  • Ripk1 and haematopoiesis: a case for LUBAC and Ripk3. Annibaldi A, Meier P. Cell Death Differ. 2018 Aug;25(8):1361-1363. doi: 10.1038/s41418-018-0135-2. PMID: 29867129
  • Checkpoints in TNF-Induced Cell Death: Implications in Inflammation and Cancer. Annibaldi A, Meier P. Trends Mol Med. 2018 Jan;24(1):49-65. doi: 10.1016/j.molmed.2017.11.002. Epub 2017 Dec 5.
  • Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1's Cytotoxic Potential. Feltham R, Jamal K, Tenev T, Liccardi G, Jaco I, Domingues CM, Morris O, John SW, Annibaldi A, Widya M, Kearney CJ, Clancy D, Elliott PR, Glatter T, Qiao Q, Thompson AJ, Nesvizhskii A, Schmidt A, Komander D, Wu H, Martin S, Meier P. Cell Rep. 2018 Apr 10;23(2):470-484. doi: 10.1016/j.celrep.2018.03.054. PMID: 29642005
  • MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death. Jaco I, Annibaldi A, Lalaoui N, Wilson R, Tenev T, Laurien L, Kim C, Jamal K, Wicky John S, Liccardi G, Chau D, Murphy JM, Brumatti G, Feltham R, Pasparakis M, Silke J, Meier P. Mol Cell. 2017 Jun 1;66(5):698-710.e5. doi: 10.1016/j.molcel.2017.05.003. Epub 2017 May 11. PMID: 28506461
  • TAT-RasGAP317-326 Enhances Radiosensitivity of Human Carcinoma Cell Lines In Vitro and In Vivo through Promotion of Delayed Mitotic Cell Death. Tsoutsou P, Annibaldi A, Viertl D, Ollivier J, Buchegger F, Vozenin MC, Bourhis J, Widmann C, Matzinger O. Radiat Res. 2017 May;187(5):562-569. doi: 10.1667/RR14509.1. Epub 2017 Mar 21. PMID: 28323576
  • TAT-RasGAP317-326-mediated tumor cell death sensitization can occur independently of Bax and Bak. Annibaldi A, Heulot M, Martinou JC, Widmann C. Apoptosis. 2014 Apr;19(4):719-33. doi: 10.1007/s10495-013-0958-8. PMID: 24362790
  • Revisiting G3BP1 as a RasGAP binding protein: sensitization of tumor cells to chemotherapy by the RasGAP 317-326 sequence does not involve G3BP1. Annibaldi A, Dousse A, Martin S, Tazi J, Widmann C. PLoS One. 2011;6(12):e29024. doi: 10.1371/journal.pone.0029024. Epub 2011 Dec 19. PMID: 22205990
  • Glucose metabolism in cancer cells. Annibaldi A, Widmann C. Curr Opin Clin Nutr Metab Care. 2010 Jul;13(4):466-70. doi: 10.1097/MCO.0b013e32833a5577. PMID: 20473153
  • Effect of RasGAP N2 fragment-derived peptide on tumor growth in mice. Michod D, Annibaldi A, Schaefer S, Dapples C, Rochat B, Widmann C. J Natl Cancer Inst. 2009 Jun 3;101(11):828-32. doi: 10.1093/jnci/djp100. Epub 2009 May 26. PMID: 19470951
  • Role of the sub-cellular localization of RasGAP fragment N2 for its ability to sensitize cancer cells to genotoxin-induced apoptosis. Annibaldi A, Michod D, Vanetta L, Cruchet S, Nicod P, Dubuis G, Bonvin C, Widmann C. Exp Cell Res. 2009 Jul 15;315(12):2081-91. doi: 10.1016/j.yexcr.2009.03.015. Epub 2009 Mar 27. PMID: 19328779
Dr. Alessandro Annibaldi CMMC Cologne
Dr. Alessandro Annibaldi

Center for Molecular Medicine Cologne | Lab. of Cell Death, Inflammation and Immunity - CMMC Research Building

CMMC - PI - JRG 12

+49 221 478-37455

Center for Molecular Medicine Cologne | Lab. of Cell Death, Inflammation and Immunity - CMMC Research Building

Robert-Koch-Str. 21

50931 Cologne

https://www.annibaldi-lab.cmmc-uni-koeln.de

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Alessandro Annibaldi

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