Peltzer, Nieves - assoc. JRG 03 and CAP 24

Cell death and inflammation are common features of many autoimmune and degenerative disorders. It is now clear that cell death can trigger chronic inflammation resulting in autoimmunity and degenerative diseases, including cancer. Therefore, understanding the crosstalk between death and inflammation is important to find effective therapies for such diseases. We aim to investigate the processes regulating the execution of cell death downstream of innate immune receptors. In particular, we want to uncover the importance of different modalities of cell death in autoimmune diseases and cancer, with the ultimate purpose to find to therapeutic strategies to tackle inflammation-dependent pathologies.
Cell death is crucial to maintain tissue homeostasis as it is important for tissue repair and infectious processes. Consequently, many organisms can sense both damage and pathogens, a deed achieved via the so-called damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) that are recognised by Pattern-recognition receptors (PRRs). The PRR family consists of Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and DNA sensors such as DNA-induced activator of interferon (IFN) (DAI, also known as ZBP1) and cyclic GMP-AMP synthase (cGAS). Triggering of PRRs results in the induction of inflammatory cytokines and chemokines including, among others, TNF, IL-1β 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- κB/MAPK-mediated gene expression, ii) apoptosis via FADD/RIPK1/caspase-8 or, iii) necroptosis via RIPK1 autophosphorylation, RIPK3 and MLKL (Fig. 1).  Recently, Caspase-8 activation by TNF was reported to induce pyroptosis via Gasdermin D and, indirectly, secondary necrosis via Gasdermin E (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.

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 (Fig. 2A). In a model of LUBAC deficiency specifically in the skin, which results in severe dermatitis due to excessive cell death (Fig. 2B), we further found that combined loss of several DRs (namely TNFR1, CD95 (Fas) and TRAIL-R), but not their individual loss, prevented chronic inflammation. Thus, we identified CD95 and TRAIL-R, in addition to TNFR1, as important DRs in cell death-induced inflammation, providing support for combining DR-inhibition as treatment of inflammation-associated autoimmunity.

The general concept is that necroptosis is highly immunogenic, due to the release of immunogenic factors such as DAMPs, whilst apoptosis is immunologically silent. However, this concept has been challenged and in certain circumstances apoptosis can also trigger immunogenicity. It is not only the mode of cell death itself to dictate immunogenicity, but also the inflammatory pathways that are concomitantly activated, and the consequent release of immunogenic factors. The decision between survival and death and the cell death programs that are activated will determine a pathophysiological outcome. Therefore, it is important to define which and how cell death processes shape immune responses in health and disease.

Autoimmune Diabetes

One common autoimmune disease with a cell death signature is Type 1 Diabetes (TID), which is caused by an immune reaction against pancreatic β-cells. However, the exact mechanisms dictating β-cell demise responsible for activating immune responses during T1D are currently poorly understood. We focus on understanding the signaling cascades that mediate cell death and inflammation in T1D and in identifying β-cell death mechanisms that induce or perpetuate immunogenicity. Diabetes is also induced by obesity. Yet, in this case, it is called Type II Diabetes (TIID) and the specific immune attack of β-cells is less clear. Instead, obesity and the associated insulin resistance ultimately lead to β-cell exhaustion which reduces β-cell mass. Again, the mechanisms of β-cell demise TIID are not entirely clear. We want to study the mechanisms dictating β-cell demise in the context of autoimmunity and obesity and find common and unique features in TI/IID.

Obesity-induced inflammation

Chronic, low-grade inflammation of adipose tissue plays a key role in the pathogenesis of obesity. Both adipocytes and the macrophages that accumulate in adipose tissue during obesity are source of inflammatory cytokines and have been identified as key components in the development of chronic inflammation and consequent insulin resistance (IR) (Fig. 3). Chronic inflammation and IR ultimately lead to Type II Diabetes (TIID). Obesity-associated inflammation is a prominent cause of cancer. Increasing adiposity leads to adipocyte death and accumulation of macrophages in the so-called crown-like structures (CLS) which has been shown to have tumor supportive functions. The type of adipocyte death that dictates the formation of tumor supportive CLS as well as the molecular mechanisms leading to adipose tissue macrophages recruitment and the type of macrophages recruited are still not completely understood. We propose to study the interplay between cell death and obesity-induced inflammation and understand the contribution of adipocyte death during obesity in metabolic syndromes and tumor microenvironment.

Cell death in cancer

Gasdermins are emerging as key determinants for antitumor immunity as well as therapy response. We are currently studying how the tumor cells regulate gasdermin expression to their own advantage. Intriguingly, tumors may use gasdermin function not only to evade cell death but also to modulate the tumor microenviornemnt. We are assessing the role of gasdermins and the impact of pharmacological modulation of gasdermin-dependent functions in small cell lung cancer (SCLC), an aggressive type of solid tumor, and in chronic lymphocytic leukemia (CLL), which is highly dependent on a tumor supportive microenvironment.

Perspectives

We aim to uncover which and how cell death pathways modulate disease outcome. By building a research programme in which basic and translational research are closely aligned we strive to link fundamental cell biology to pathophysiological mechanisms to develop novel treatments options for patients.

Lab Website

For further information please check the Peltzer Lab - Cell Death and Inflammation in Health and Disease webpage.