Peter Vandenabeele is senior full professor at the Inflammation Research Center (IRC), a VIB department at the Ghent University. He recently published in Nature an original research paper on the regulation of cell survival in vivo (Takahashi et al., 2014). RIPK1 (receptor interacting protein kinase 1) plays an important role both in the survival as well as in the death of epithelial cells. Full knockout mice for the Ripk1 gene are not viable. The team of Vandenabeele managed to make a viable conditional mouse model that lacks Ripk1 only in the intestinal epithelial cells. They also obtained in collaboration with people from GSK (Pennsylvania) a mouse model containing a mutant form of RIPK1 that lacks the kinase activity. Thanks to these genetic mouse models, mechanisms that regulate cell survival and cell death could be explored. Peter Vandenabeele and his team found that the platform function of RIPK lacking the kinase activity is associated with cell survival, while the kinase activity is associated with induction of cell death. Peter Vandenabeele also published a review paper in Nature about cell death pathways and inflammation in early 2015 (Pasparakis and Vandenabeele, 2015).
Peter Vandenabeele and Nozomi Takahashi, the senior postdoc who contributed mainly to the Nature article.
Cell death is a normal and necessary cellular process for life in multicellular organisms. It is crucial for the development of organs, tissue homeostasis and many other physiological processes, such as lymphocyte selection in the immune system. Every second, about one million cells die in our body, which are replaced by new cells. Furthermore, cell death is important to clear bacteria and viruses from the body. Cell death can also be linked with cellular stress, injury or infection. Unbalanced cell death is associated with many diseases. Too much or too sensitive cell death is seen in inflammatory and degenerative diseases, while too little or insensitive cell death is very often related to cancer. Therapeutic strategies can be envisioned that either sensitize or desensitize a cell death pathway. Of course, this requires profound knowledge of the cell death pathway and the underlying molecular and regulatory mechanisms.
Apoptosis and regulated necrosis
Up to now it was believed that apoptosis was the only form of regulated cell death. Apoptosis is characterized by blebbing, cytoplasmatic schrinkage, chromatin condensation, nuclear fragmentation and shedding of apoptotic bodies. The apoptopic bodies are recognized and rapidly cleared by phagocytes. Necrosis was seen as a non-regulated accidental form of cell death due to infection, injury or trauma. Characteristics of necrosis are: increased cell volume, increasingly translucent cytoplasm and permeabilization of the cell membrane resulting in an uncontrolled release of cell debris into the extracellular space. This evokes an inflammatory response. Recent studies have shown that necroptosis is a highly regulated form of necrosis and might play an important role in the pathogenesis of several human diseases, such as chronic inflammatory diseases.
Learn more about apoptosis and necrosis in this movie by Vandenabeele:
One can envision multiple applications for targeting regulated necrosis. Several pharmaceutical companies have started large R&D programs to develop inhibitors of RIP kinases in order to block inflammation elicited by cell death. Studies show that administration of RIP kinase inhibitors has a favorable effect on sepsis. These inhibitors presumably block necroptotic cell death. Cell death in barrier tissue, such as intestines or skin, leads to barrier loss and increased inflammation. As a consequence, interfering in cell death pathways by manipulating RIP kinases might counteract inflammatory bowel disease.
Activation of RIP kinases could also be useful to sensitize cell death pathways. For example, cancer cells often develop anti-apoptotic resistance after therapy. Activation of RIP kinases can induce necroptosis and circumvent the anti-apoptotic survival mechanism of cancer cells and in this way kill them.
Vandenabeele and his unit have the ambition to target compounds that can induce the survival conformation of RIPK1 and protect cells that suffer from all different kinds of cellular stress. He hopes that that these insights yield new therapeutic opportunities to treat acute and chronic inflammatory conditions.
Pasparakis, Manolis, and Peter Vandenabeele. "Necroptosis and its role in inflammation." Nature 517.7534 (2015): 311-320.
Takahashi, Nozomi, et al. "RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis." Nature 513.7516 (2014): 95-99.
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