Immune cells have a remarkable ability to seek out infections, similar to how sniffer dogs operate, thanks to specialized sensors known as Toll-like receptors, commonly abbreviated as TLRs. However, the specifics of what activates TLRs, as well as how the intensity and type of activation relates to what is being detected, remain areas of investigation. A recent study conducted by researchers from the University of Bonn and the University Hospital Bonn (UKB) aimed to shed light on these questions using a new approach. Their findings could significantly accelerate the development of treatments for infectious diseases, cancer, diabetes, and dementia, and have been published in the journal Nature Communications.
TLRs are present in large quantities on the surfaces of various cells, particularly those located in mucous membranes and immune cells. Much like the olfactory receptors in our nose, TLRs activate upon encountering certain chemical signals. This activation sets off a cascade of reactions within the cells. For example, when scavenger immune cells detect a bacterium, they initiate a process known as phagocytosis by engulfing and breaking it down, while other immune cells dispatch chemical messengers to summon additional help, thereby triggering inflammation.
Responses Triggered by Danger Signals via TLRs
TLRs consist of several categories, each responding to distinct “odors.” According to Professor Günther Weindl from the Pharmaceutical Institute at the University of Bonn, “These molecules have evolved over time into vital danger signals.” One prominent example is lipopolysaccharides (LPS), which are essential components of a bacterium’s cell wall.
Weindl notes, “In many instances, we still lack clarity regarding the specific responses activated when a signal is detected.” He adds, “It’s quite possible that various molecules can activate the same TLR but result in different reactions.”
To investigate these responses, researchers typically label molecules with different colors to track the specific signaling pathways activated when certain receptors are engaged. However, this approach can be both time-consuming and labor-intensive, requiring extensive knowledge of the existing signaling pathways.
Weindl and his team instead explored an alternate technique that does not rely on color-coding and has previously been successful with other receptor studies. This innovative method examines how cells change shape upon encountering signal molecules, preparing themselves to either absorb bacteria or transform into infected tissue.
Visualizing TLR Activation through Wavelength Changes
This morphological change can be easily observed by placing the cells on a specially coated clear plate and illuminating them from below with a broadband light source. The specific wavelengths reflected when light strikes the coating depend on the ongoing processes and transformations within the cell.
Dr. Janine Holze, a colleague of Weindl, explains, “We showed that these changes in reflected wavelengths occur just minutes after introducing the signal molecule.” They also tested cells with lipopolysaccharides from E. coli and Salmonella. Although both trigger the same TLR, the reflected light spectrum exhibited different changes post-introduction of the respective E. coli LPS and Salmonella LPS. This observation indicates that the same receptor can be activated differently by distinct molecules, leading to tailored responses based on the signal.
Weindl concluded, “This method provides a far more intricate understanding of receptor function and simplifies the process of searching for potential drugs with precise action profiles.” There are exciting possibilities, such as enhancing the immune response to empower the body to better combat cancer cells. Conversely, in conditions like diabetes, rheumatism, or Alzheimer’s, the goal could be to downregulate specific immune responses that might harm healthy tissues, potentially taking researchers closer to this objective through the utilization of their new method.
This study received funding from the German Research Foundation (DFG).
