A study led by the University of Barcelona opens new perspectives to better understand how the molecular mechanisms involved in regenerative medicine work. The study focuses on tumor necrosis factor-α (TNF-α) and its receptors TNFR, molecules of great interest in biomedicine due to their involvement in multiple diseases such as obesity related to diabetes mellitus type 2, inflammatory bowel diseases and several types of cancer. .
The research, highlighted in the News & Views part of The EMBO journal , is led by Professor Florenci Serras, from the Faculty of Biology and the Institute of Biomedicine of the University of Barcelona (IBUB). The work also involves experts from the UB’s Biodiversity Research Institute (IRBIO), the Center for Genomic Regulation (CRG) and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS).
“In particular, the secreted tumor necrosis factor can recognize and bind to its receptor TNFR, which is located on the membrane of neighboring cells. As a result of the binding, the TNFR receptor is activated and regulates processes as diverse as cell proliferation, death and adaptive immunity,” explains Florenci Serras, member of the UB Department of Genetics, Microbiology and Statistics.
The findings indicate that tumor necrosis factor-α (TNF-α) – a protein that modulates cellular activity – has two TNFR receptors that can exhibit completely opposite functions in response to biological tissue injury: specifically, one receptor improves cell survival and regeneration, while the other can promote cell death.
The research, conducted using the Drosophila melanogaster study model, could contribute to the design of TNFR receptor agonist and antagonist molecules that stimulate epithelial tissue regeneration in patients with severe burns, or affected by inflammatory bowel disease and some cancers.
Drosophila: a model for studying human disease
Communication between cells is a decisive process in the development and physiology of organisms. One of the routes of cell communication is the secretion of molecules – for example tumor necrosis factor (TNF-α) – that have specific functions in biological cells, tissues and organs.
“In particular, the secreted tumor necrosis factor can recognize and bind to its receptor TNFR, which is located on the membrane of neighboring cells. As a result of the binding, the TNFR receptor is activated and regulates processes as diverse as cell proliferation, death and adaptive immunity,” explains Florenci Serras, member of the UB Department of Genetics, Microbiology and Statistics.
In the genome of mammals there are nineteen TNF molecules and twenty-nine TNFR receptors, which reveals the great complexity of their research in the case of the human species. Some organisms, such as the D. melanogaster flies have only one tumor necrosis factor (called Eiger, Egr) and only two TNFRs, namely the Grindelwald (Grnd) and Wengen (Wgn) receptors.
“Thanks to this simplicity and adding the multiple genetic tools of Drosophilawe have been able to use this model organism to study the regulation and function of TNF-α/TNFR,” says the researcher.
Receptors with opposite functions
Although TNF-α and TNFR receptors are linked to acute and chronic diseases, “it is still not well understood how these components regulate such opposing cellular processes, such as cell death or cell survival, and even cell proliferation,” Serras points out.
This study, which will be included in the dissertation that PhD candidate José Esteban-Collado will defend, provides evidence supporting the different and opposing functions of TNFR Grnd and Wgn. “On the one hand, the Grnd receptor promotes cell death (apoptosis) to eliminate damaged cells via a TRAF2-dTAK1-JNK signaling pathway in a TNF-α Egr-dependent manner,” says Serras. “In contrast, the Wgn receptor promotes cell survival and regeneration to keep tissues healthy and in good condition, via the TRAF1-Ask1-p38 signaling pathway and without the need for TNF-α Egr,” he adds.
“That is, the first receptor needs the ligand to bind to the receptor, while the second can be activated without interaction with the ligand. Therefore, each TNFR promotes its signaling to achieve different functions,” explains Florenci Serras. “The communication mechanisms of TNFRs must therefore generate a balance between the activities of the different TNFRs, the molecular signals that set them in motion and their dependence – or not – on the ligand (TNF-α),” he points out.
Damaged cells release molecular signals into healthy cells
When a cell dies or becomes damaged, it communicates with healthy cells to replace the non-functional cell with a new one and initiate regeneration of the affected tissue. The research describes how dying cells release reactive oxygen species (ROS), which pick up functional cells in their environment to drive the regeneration process of the affected tissue.
“In a pathological situation or tissue damage, both receptors show different responses. First, the affected tissue produces TNF-α Egr, which binds to Grnd on the membrane. This is internalized and promotes suicide by cell death (apoptosis). At the same time Over time these cells produce ROS, which spread and reach healthy cells as an alarm signal indicating tissue deterioration,” explains Serras “The ROS signal activates Wgn directly in healthy cells, without the need for Egr, and consequently activates the signaling pathway that controls the. promotes tissue survival, protection and regeneration,” notes Serras.
The results of the new study support the model in which ROS from damaged tissue can activate Wgn-dependent signaling in healthy surrounding cells to promote their regeneration.
Using an elegant binary system that allows manipulation of a gene in tissue-specific domains, the authors also determined an essential role for TNFR Wgn – but not Grnd – in p38 kinase activation. “In healthy cells, this p38 will be responsible for setting in motion the entire genetic machinery for tissue repair,” concludes Florenci Serras.
