Inflammatory responses protect the body from microbial infections and promote wound healing and tissue regeneration. However, excessive or prolonged inflammation causes tissue damage and is involved in the pathogenesis of many diseases. The team of Prof. Dr. Manolis Pasparakis studies the mechanisms regulating inflammation and the development of inflammatory diseases. Their research revealed the important role of cell death as a trigger for inflammation in epithelial tissues such as the skin and the intestine. Their long-term goal is to understand the mechanisms that control inflammation and contribute to the pathogenesis of chronic inflammatory diseases.
Our research: Healthy tissue homeostasis is maintained by balanced interactions between epithelial, stromal and immune cells with the commensal microbes that normally reside on the surface of our barrier tissues such as the gut and the skin. Disruption of tissue homeostasis can cause chronic inflammatory diseases and in some cases also cancer. Despite recent progress in identifying factors that contribute to tissue damage and chronic disease, the causes that initiate pathogenic inflammatory responses remain unknown. As a consequence, currently available therapies mainly target the symptoms and aim to achieve stable suppression of the inflammatory response, which requires chronic treatment that causes side effects and increases costs. The group studies the mechanisms that regulate immune responses, with particular interest on identifying molecules and pathways that are responsible for causing chronic inflammatory diseases. They have a long-standing interest on understanding how NF-κB signalling contributes to disease pathogenesis.
More recently, they have been interested in studying how different pathways of regulated cell death, such as apoptosis or necroptosis, may contribute to inflammation and the pathogenesis of inflammatory diseases.
Our successes: The group's recent studies contributed to the identification of new mechanisms causing inflammation in epithelial tissues, which may lead to the development of new treatments for inflammatory diseases. Their experiments showed that death of epithelial cells triggers severe chronic inflammation in barrier tissues such as the gut and the skin. In particular, their results revealed that necroptosis, a newly identified pathway or regulated necrotic cell death, of intestinal epithelial cells triggered severe colon inflammation resembling human colitis. In addition, the experiments showed that necroptosis of epidermal keratinocytes also triggered severe skin inflammation. Furthermore, the most recent studies revealed novel functions of RIP kinase 1 that are important for the regulation of epithelial cell survival and the maintenance of immune homeostasis in barrier tissues.
Our goals: The long-term goal is to understand the mechanisms that regulate immune homeostasis and control inflammation. The group's current work focuses on the mechanisms regulating cell death and particularly necroptosis and how this pathway of regulated necrosis contributes to inflammation. Using genetic mouse models, they aim to identify basic mechanisms regulating cell death and inflammation. In addition, they aim to assess the potential role of necroptosis in the pathogenesis of human diseases and explore the possible therapeutic application of necroptosis inhibitors in chronic human inflammatory diseases.
Our methods/techniques: Prof. Pasparakis and his team use genetic mouse models to study the molecules and pathways regulating inflammation and are responsible for the pathogenesis of inflammatory diseases. Since these pathways are conserved between mice and humans, their results are relevant for the better understanding of the mechanisms causing human inflammatory diseases. In addition, they analyze human patient samples in order to assess whether the mechanisms identified to cause disease in mouse models also contribute to the pathogenesis of inflammatory diseases in human patients.
Figure 1: Mice with intestinal epithelial specific knockout of FADD (FADDIEC-KO) show necroptosis of intestinal epithelial cells and develop severe inflammatory colitis. Genetic deficiency of RIPK3 inhibits epithelial cell necroptosis and prevents the development of colitis in FADDIEC-KO mice.
Figure 2: Mice with epidermal keratinocyte specific knockout of RIPK1 (RIPK1E-KO) show necroptosis of keratinocytes and develop severe skin inflammation characterized by epidermal hyperplasia, increased expression of keratin 14, and decreased expression of keratin 10. Genetic deficiency of RIPK3 prevents keratinocyte necroptosis and inhibits skin inflammation in RIPK1E-KO mice.