Medicine 1

Head of Department:
Prof. Dr. med. Markus F. Neurath

Laboratory of Mucosal Immune Regulation and Intestinal Cell Biology (Prof. Dr. rer. nat. Christoph Becker)

Current Reserarch Projects of our Group

Regulation of programmed necrosis (Necroptosis)

Until recent years, the term programmed cell death and apoptosis were used interchangeably, since only in this form of cell death, the cell itself determines the procedures and performs a kind of suicide program. Necrosis in contrast was referred to as an uncoordinated (passive) form of cell death induced by irreversible cell damage, such as following mechanical injury and cytotoxins, due to thermal influences or pathogens. Both apoptosis and necrosis can be differentiated microscopically based on morphological characteristics.

Through research findings in recent years, however, a novel form of cell death, denoted necroptosis, was identified and subsequently characterized. Interestingly, necroptosis combines both apoptotic and necrotic features. Morphologically necroptosis cannot be distinguished from necrosis. On the other hand, it is clearly distinguishable from that, because it is not a passive process, such as necrosis, but can be triggered by regulated cellular pathways. The underlying molecular mechanisms correspond strongly to those of apoptosis, since both processes are regulated by similar intracellular protein complexes.

The first indication of this new form of cell death was obtained by studies, in which the physiological relevance of apoptosis was to be explored in vivo. These studies led to the finding that the molecules FADD and caspase-8, in addition to their classical function as initiators of apoptosis had additional apoptosis-independent functions in fact promoting cell survival under certain circumstances. Around the same time, again under certain experimental conditions following apoptosis induction, researchers were able to observe cells that morphologically strongly differed from apoptotic cells. What they observed were cells with swollen cytoplasm and cell organelles, yet with intact nuclei, typical features of necrotic cells. Thus, these researchers were able to show that a controlled activation of the extrinsic apoptosis pathway can cause cell death morphologically corresponding to necrosis. This form of cell death is now known as necroptosis. Through complementary in vitro experiments researchers were finally able to identify the underlying necroptosis inducing molecules. These belong to the family of kinases and include the "receptor-interacting-protein 1 (RIPK1), RIPK3, and the protein MLKL (mixed lineage kinase domain-like protein). Under physiological conditions, the activation of these proteins is blocked by caspase-8. When caspase-8 activity itself is blocked through genetic deletion of the enzyme, pharmacological methods or cellular inhibitors (e.g. cFLIPs), inactivation of RIPK1 by caspase-8 cannot be maintained. If RIPK3 Is expressed in the same cell, it can then interact with RIPK1, a process that initiates autophosphorylation of both kinases. This in turn leads to the phosphorylation and activation of MLKL and ultimately to necroptosis.

Relevance of Cell Death Regulation in the Development of Gut Inflammation and Cancer

Our data indicate that both activation and inhibition of caspase-8 mediates alternative modes of programmed cell death (see figure). It therefore requires a strict control of the expression and activity of caspase-8 to warrant cell survival. Since the discovery of necroptosis, the participation of this form of cell death was demonstrated in various pathophysiological processes. With our own work we have contributed significantly to the understanding of the importance and regulation of necroptosis. Our current projects investigate the pathophysiological relevance of necroptosis and its regulation in diseases of the intestine.

Regulation of Intestinal Epithelial Cells by the Mucosal Immune System