A study conducted by the University of Barcelona focused on tumour necrosis factor-α (TNF-α) and its receptors TNFR to better understand the molecular mechanisms involved in regenerative medicine. The study, led by Professor Florenci Serras and involving experts from various research institutes, explores the role of TNF-α and TNFR in diseases such as obesity related to type 2 diabetes, inflammatory bowel disease, and cancer. The research, highlighted in The EMBO Journal, investigates how TNF-α interacts with its receptors on cell membranes to regulate processes like cell proliferation, cell death, and immunity.
The findings of the study suggest that TNF-α has two receptors, TNFR, which can have opposite functions in response to tissue injury. One receptor enhances cell survival and regeneration, while the other can promote cell death. By utilizing the Drosophila melanogaster model organism, the study could pave the way for developing molecules that stimulate tissue regeneration in patients with conditions like severe burns, inflammatory bowel disease, and cancer. The simplicity of the Drosophila model, with only one TNF molecule and two TNFR receptors, allows for a better understanding of the TNF-α/TNFR system.
Cell communication is a crucial process in organism development and physiology, with molecules like TNF-α playing specific roles in cells, tissues, and organs. The study demonstrates that TNF-α can bind to its receptor on neighbouring cells, activating various processes like cell proliferation, cell death, and immunity. While the mammalian genome has multiple TNF molecules and receptors, the Drosophila fly model offers a simpler system for studying TNF-α/TNFR regulation and function. This research, part of a doctoral thesis, sheds light on how TNFR receptors can have different signaling pathways and functions in response to tissue damage.
The study reveals that TNFR receptors like Grindelwald (Grnd) and Wengen (Wgn) can have opposing functions in regulating cell death, survival, and proliferation. The Grnd receptor promotes cell death through specific signaling pathways in response to TNF-α, while the Wgn receptor promotes cell survival and regeneration independently of TNF-α. This balance between the activities of different TNFRs, the signals they produce, and their dependence on TNF-α is crucial for cellular processes like tissue repair and regeneration. The research highlights the importance of understanding the communication mechanisms of TNFRs in achieving different cellular functions.
When damaged cells release molecular signals in healthy cells, it triggers a response to replace the damaged cell and initiate tissue regeneration. Dying cells release reactive oxygen species (ROS) that healthy cells use as an alarm signal to promote tissue regeneration. In pathological or damaged tissue, TNF-α Egr binds to Grnd receptors, leading to cell death through apoptosis. At the same time, ROS from damaged cells can activate Wgn receptors in healthy cells, initiating a signaling pathway that promotes tissue survival and regeneration. This process highlights the role of TNFR receptors in coordinating tissue repair and regeneration in response to tissue damage.
Through an elegant binary system allowing targeted gene manipulation, the study establishes the essential role of TNFR Wgn in activating the p38 kinase that promotes tissue repair in healthy cells. The signaling pathways initiated by TNFRs in response to tissue damage support the model where ROS from damaged cells trigger regeneration in surrounding healthy cells. By understanding how TNFR receptors like Wgn play a crucial role in tissue repair and regeneration, the research opens new possibilities for designing therapies targeting TNF-α/TNFR signaling to promote tissue regeneration in patients with various diseases.
