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’ advantage.
Organisms can sense both damage and pathogens via the so-called damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) that are recognised 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-signalling output is skewed towards inflammation/survival; however, in autoimmune disorders or pathological conditions this balance is shifted towards cell death induction.
Our group studies how 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.
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 programmes, is currently poorly understood.
We aim to study the mechanisms regulating cell death in i) β-cell in the context of autoimmune diabetes, ii) adipocytes, in the context of obesity and iii) cancer and tumor microenvironment, with a particular interest in small cell lung cancer. One of the main focus of the lab is to explore the interplay between cell death and obesity-induced inflammation and understand the contribution of adipocyte death during obesity in metabolic syndromes (including T2D) and in the tumor microenvironment (Fig. 3).
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 characterisation of the role of different programmed cell death programmes in health and disease.
We aim to uncover which, and how, cell death pathways modulate disease outcome. We aim to build a research programme in which basic and translational research are closely aligned so as to be able to translate fundamental discoveries on the mechanism and aetiology of disease into novel treatments options for patients.
