Associated Principal Investigator, Department of Translational Genomics
Cell death is important for physiological processes, such as embryonic development, immune tolerance, fight against pathogens, etc. However, uncontrolled cell death can lead to chronic inflammation, tissue damage and autoimmunity. Cell death-induced chronic inflammation is also associated with cancer. Different cell death programmes release specific factors that impact on immune responses and tumorigenesis in a distinctive manner. Our goal is to study the impact of different forms of programmed cell death on disease pathogenesis and to exploit this knowledge for therapeutic purposes by controlling the levels of cell death and by rewiring cell death programs to the host’s advantage.
Our research: Organisms can sense both damage and pathogens via the so-called damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) that are recognized by Pattern-recognition receptors (PRRs). Triggering of PRRs results in the induction of inflammatory cytokines and chemokines including, among others, TNF, IL-1b and type I IFNs. These cytokines play crucial roles in triggering innate immune responses by binding to their respective receptors, including TNF receptor (TNFR) superfamily (SF) members.
Binding of TNF to its cognate receptor TNFR1 results in downstream cascades that induce: i) inflammation/survival via LUBAC and cIAP1/2 by activating NF-kB/MAPK-mediated gene expression, ii) apoptosis via FADD/RIPK1/caspase-8 or, iii) necroptosis via RIPK1 autophosphorylation, RIPK3 and MLKL (Fig. 1). In normal physiology, TNFR1-signaling output is skewed towards inflammation/survival; however, in autoimmune disorders or pathological conditions this balance is shifted towards cell death induction.
Our group studies show that different modes of inflammatory cell death induced by immune receptors impact on autoimmunity, chronic inflammation, and tumorigenesis. One aspect of our research plan focuses on the role of cell death in inducing or perpetuating autoimmunity in a model of Type I Diabetes. Another aspect is the study of cell death in obesity-induced inflammation and its associated metabolic complications such as insulin resistance and Type 2 Diabetes (T2D). We are also interested in understanding how tumor cells regulate cell death programs to their own advantage and design strategies to characterize new tumor suppressors but also to discover novel tumor vulnerabilities.
Our successes: In the past years, we discovered that the linear ubiquitin chain assembly complex (LUBAC), an E3 ligase that generates linear ubiquitin chains on components of many immune receptor-signaling complexes, is crucial for survival as it prevents both apoptosis and necroptosis of endothelial cells during embryogenesis (Fig. 2A) (Peltzer, Nature 2018). We further observed that inhibiting cell death in a model of dermatitis, driven by LUBAC deficiency in the skin (Fig. 2B), prevents inflammation and disease progression (Taraborrelli, Peltzer et al., Nature Communications 2018). Both studies show that not only necroptosis, but also apoptosis can induce inflammation. These studies challenge the current understanding of apoptosis as an immunologically silent mode of cell death. Whether apoptosis induces inflammation directly or via crosstalk with other inflammatory cell death programs, is currently poorly understood.
Our goals: We aim to study the mechanisms dictating β-cell death in the context of autoimmunity and during obesity, and find common and unique features in T1/2D. Furthermore, we aim to explore the interplay between cell death and obesity-induced inflammation and to understand the contribution of adipocyte death during obesity in metabolic syndromes (including T2D) and in the tumor microenvironment (Fig. 3). Our mission is to understand disease aetiology at the molecular level to identify potential treatments for autoimmune and inflammation-driven disorders, including cancer.
Our methods/techniques: Our laboratory has a number of genetically engineered mouse models to underpin the role of cell death in different pathophysiological conditions. This is combined with a wide range of imaging, molecular, and cell biology approaches for mechanistic characterization of the role of different programmed cell death programs in health and disease.
Figure 1: TNFR1 signaling outputs. In normal physiology, TNF induced inflammation and survival; however, in pathological conditions this balance is shifted towards cell death. Cell death can be induced by caspase-8-mediated apoptosis or RIPK3/MLKL-mediated necroptosis. Necroptosis additionally requires the kinase activity of RIPK1. LUBAC and cIAP1/2 are crucial regulators of TNFR1-signaling output by preventing cell death.
Figure 2: LUBAC maintains tissue homeostasis by preventing cell death.
A. Loss of LUBAC in the whole-body results in embryonic lethality (upper panel) due to disruption of yolk sac vasculature (upper and middle panel). Excessive cell death is detected in endothelial cells which causes the defects in vascularization (lower panel). (Peltzer, N., et al. Cell Reports 2014, Peltzer, N., et al. Nature 2018)
B. Loss of LUBAC in the epidermal keratinocytes results in severe skin inflammation (upper and middle panels). Excessive cell death is observed in inflamed skin (lower panel) and is the cause of dermatitis (Taraborrelli, L., Peltzer, N., et al. Nature Communications 2018)
Figure 3: Obesity induced inflammation and associated complications. Scheme of the intertwined consequences of obesity-induced inflammation in metabolic diseases and cancer that are of interest for our research group.