A recent study provides fresh insights into the molecular mechanisms that play a vital role in regenerative medicine. This research concentrates on tumor necrosis factor-α (TNF-α) and its associated receptors, known as TNFRs. These molecules are significantly important in the field of biomedicine due to their connections to various diseases, including obesity linked to type 2 diabetes, inflammatory bowel disease, and multiple cancer types.
New research led by the University of Barcelona sheds light on the molecular mechanisms underpinning regenerative medicine. The focus of this study is on tumor necrosis factor-α (TNF-α) and its receptors, TNFR, which are crucial in biomedicine due to their roles in various illnesses such as obesity associated with type 2 diabetes mellitus, inflammatory bowel disease, and different cancers.
The study, featured in the News & Views section of The EMBO Journal, is directed by Professor Florenci Serras from the Faculty of Biology and the Institute of Biomedicine at the University of Barcelona (IBUB). It also includes the collaboration of experts from the University’s Biodiversity Research Institute (IRBIO), the Centre for Genomic Regulation (CRG), and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS).
According to Florenci Serras, a member of the Department of Genetics, Microbiology, and Statistics at UB, “The secreted tumor necrosis factor can detect and attach to its receptor, TNFR, found on the surface of adjacent cells. This binding activates the TNFR receptor and regulates various processes including cell growth, apoptosis (cell death), and adaptive immunity.”
The research findings suggest that the protein TNF-α, which modulates cellular activities, has two TNFR receptors that can produce entirely opposite effects when faced with injury to biological tissues. Specifically, one receptor promotes cell survival and healing, while the other can trigger cell death.
Utilizing the Drosophila melanogaster model, this study holds potential for informing the development of agonists and antagonists of TNFR receptors, which could enhance the regeneration of epithelial tissues in individuals suffering from severe burns, inflammatory bowel disease, or certain cancers.
Drosophila: A valuable model for human disease research
The interaction between cells is crucial for the growth and normal functioning of organisms. A pathway for this communication is the secretion of specific molecules, such as tumor necrosis factor (TNF-α), which serve dedicated roles in biological cells, tissues, and organs.
Serras elaborates, “The secreted TNF can find and bind to its receptor TNFR located on neighboring cells’ membranes. This interaction leads to the activation of the TNFR receptor, affecting various processes like cell proliferation, cell death, and adaptive immunity.”
The mammalian genome contains nineteen TNF molecules and twenty-nine TNFR receptors, highlighting the complexity of their interactions in humans. In contrast, organisms like the D. melanogaster only possess a single tumor necrosis factor (known as Eiger, or Egr) and just two TNFRs, called Grindelwald (Grnd) and Wengen (Wgn).
“Due to this simplicity, along with the various genetic tools available for Drosophila, we have leveraged this model organism to investigate TNF-α/TNFR regulation and function,” says the researcher.
Receptors with contrasting roles
Despite TNF-α and TNFRs being implicated in both acute and chronic diseases, “the exact mechanics of how these components govern such conflicting cellular processes as survival versus death remain poorly characterized,” Serras points out.
This research, which will contribute to the PhD dissertation of student José Esteban-Collado, provides evidence for the distinct and opposing roles of the TNFRs Grnd and Wgn. “The Grnd receptor facilitates programmed cell death (apoptosis) to remove damaged cells through a specific TRAF2-dTAK1-JNK signaling pathway, which depends on TNF-α Egr,” explains Serras. Conversely, he notes that the Wgn receptor supports cell survival and tissue regeneration, engaging the TRAF1-Ask1-p38 signaling pathway independently of TNF-α Egr.
Serras elaborates, “Essentially, the first receptor relies on ligand binding for activation, while the second can initiate signaling without the need for interaction with the ligand. Thus, each TNFR directs its signaling to fulfill distinct roles.” He emphasizes that TNFR communication mechanisms must create a balance between the actions of differing TNFRs, the molecular signals they trigger, and their dependence—or lack thereof—on the ligand (TNF-α).
Molecular signals from damaged cells to healthy ones
When cells are dying or damaged, they send signals to healthy cells, prompting the latter to replace the non-functioning cells and begin tissue regeneration. The research outlines how dying cells emit reactive oxygen species (ROS), which healthy surrounding cells detect to initiate the regeneration of affected tissues.
Serras clarifies, “In a pathological context or following tissue injury, each receptor exhibits different responses. Initially, the compromised tissue generates TNF-α Egr, which binds to Grnd on the surface of cells. This interaction is internalized, leading to programmed cell death (apoptosis). Simultaneously, these dying cells release ROS, which act as alarm signals for neighboring healthy cells regarding tissue damage.” He adds, “The ROS then directly activates Wgn in the healthy cells, without requiring Egr, sparking a protective signaling cascade that ensures tissue survival and regeneration.”
The new study’s findings support a model where ROS from damaged tissue can trigger Wgn-dependent signaling in surrounding healthy cells to foster tissue regeneration.
Utilizing a sophisticated binary system that allows for gene manipulation in specific tissue areas, the researchers also identified a critical role for TNFR Wgn—but not Grnd—in activating p38 kinase. Serras concludes, “In healthy cells, p38 is vital for initiating the complete genetic machinery necessary for tissue repair.”
