Systems-Oriented Immunology and Inflammation Research
In the course of evolution, organisms that consist of more than one cell have developed various mechanisms for killing their own cells in a targeted manner. These mechanisms are triggered according to occasion and cell type and are acutely sensitive to environmental influences. Such a “suicide program” for cells is called apoptosis. It is responsible for the elimination of injured, old, mutated or dangerous cells, as well as for self-regulation of tissues.
And it plays an important role in the interaction between pathogens and the host cell. For example, immune cells induce apoptosis in infected tissue cells in order to inhibit further reproduction of the pathogens – because viruses cannot reproduce in dead cells. On the other hand, certain viruses and bacteria can also inhibit apoptosis in the host cell, in order to ensure their own survival.
Also, when regulation of apoptosis within the organism has been disabled, illnesses can arise. If, for example, apoptosis is too limited, a breakdown of tolerance mechanisms and ultimately auto-immune disease can occur; this disease causes the immune system to turn on the organism itself. In order to better understand these mechanisms, we are decoding these signaling pathways, which regulate the apoptosis in the cells of the immune system.
Regulation of apoptosis
Since it is a matter of life and death, apoptosis has to be tightly regulated. One important regulator of apoptosis is c-FLIP. Using mouse models, we demonstrated that enforced expression of c-FLIP leads to a better immune response to bacterial infections. However, prolonged c-FLIP expression also resulted in autoimmune disease in aged mice. Furthermore, we showed that c-FLIP is essential for the survival of regulatory T cells and, thus, for immune tolerance. Therefore, we are currently screening for chemical compounds that can modulate c-FLIP activity.
Another important anti-apoptotic factor is the transcription factor NF-kB, which is also a crucial regulator of inflammation. In that regard, we investigate the regulation of NF-kB by so-called atypical IkB proteins (for further information please see projects).
Other forms of cell death
Next to apoptosis, which is an ordered fragmentation of the cell leading to phagocytosis of the cell’s remains and suppression of an immune response, there are several necrotic forms of cell death. The latter are characterized by membrane rupture and leakage of cellular content, which leads to inflammation. One well-characterized form of programmed necrosis is necroptosis that is mediated by RIP kinases. Necroptosis and apoptosis can regulate each other.
Autophagy is a catabolic mechanism that is important for many biological processes such as activation of immune cells. It also functions as a kind of cell-autonomous immunity. On the molecular level, autophagy is executed by so-called AuTophaGy-related (ATG) proteins. We showed that infection with Staphylococcus aureus induces selective autophagy. Intracellular S. aureus gets associated with ubiquitin and recruited via autophagy receptors such as SQSTM1/p62 into autophagosomes. However, S. aureus evades autophagic degradation by activating p38 MAPK of the host, degradation of the autophagosomal membranes and escape into the cytoplasm. We believe that this is an important mechanism how S. aureus can persist in the host. Therefore, we will further investigate the interplay between S. aureus infection and autophagy in the future.
Bachelor & Master
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- Gas und Bremse für ImmunantwortenUnser Immunsystem ist geprägt durch ein kompliziertes Wechselspiel unterschiedlicher Immunzellen, das Wissenschaftler stückchenweise verstehen lernen. Um das Immunsystem daran zu hindern, dass es sich gegen uns selbst richtet oder um ihm auch mal einen Schubs geben zu können, müssen sie die molekularen Stellknöpfe finden – und beeinflussen. Einen dieser Stellknöpfe haben Ingo Schmitz und Marc Schuster entdeckt. Folgen Sie den beiden ins Labor...