Zebrafish and Humans Have More in Common than You Think
Dr. Stepheny Zani - 26 March 2026
Redness, itching and swelling. Those living with contact dermatitis know by heart the signs of an allergic reaction. Induced by underlying inflammation, it is one example of how the innate immunity (the defense system we are born with) works to protect the body against foreign substances or pathogens.
Innate immunity is part of our daily lives, preventing cuts from getting infected and neutralizing particles inhaled or ingested. The body recognizes foreign particles and pathogens via receptors that bind to ligands, such as metals e.g. nickel, or substances attached to the surface of microorganisms, such as lipopolysaccharides (LPS). Once the foreign particle is identified the defense mechanisms are activated to neutralize and eventually get rid of it.
The first group of receptors identified to mediate innate immunity was the Toll-like receptors (TLR) family. They are named with unique numbers, such as TLR1, TLR2 and so on. Many TLR are similar between humans and other species, for example, TLR4 is shared between humans, rodents, and zebrafish!
In mammals, TLR4 is specially involved in metal-induced allergies (or hypersensitivity), where the body has an exacerbated reaction upon contact with certain metals. For example, if someone allergic to nickel wears costume jewelry for prolonged periods, the metal activates the TLR4 causing exacerbated inflammation. The same cascade activates during an infection with bacteria containing LPS. In essence, TLR4 acts as an alarm to protect the body against pathogens and toxins.
But what about zebrafish? It’s an easily accessible model to study immune-related mechanisms in the laboratory as this model allows for real time tracking of immune cell migration and immune response. But could the immune function be similar enough to mammals? Intrigued by that question, Aaron P. D. Fox (supervised by Dr. W. Ted Alisson) investigated whether zebrafish would respond to metal induced toxicity similarly to humans.
Using fluorescence to measure cell viability after exposure to certain metals, Allison and his team revealed TLR4 mediates metal-induced toxicity in zebrafish. Upon exposure to nickel, cobalt, and platinum, TLR4 activation induced reactive oxygen species formation, inflammation, and mitochondria dysfunction, causing cellular death. Working with Tracy S. Lee (supervised by Dr. Amit P. Bhavsar), the group further showed that zebrafish TLR4 receptors could substitute for their human counterparts in mammalian cells.
With all of that known, it was time to compare with other species. It turns out, only mammals have been reported as displaying the same reaction. Not only was the zebrafish a good model, it appeared to be a relevant model as well. Indeed, the team is very optimistic that zebrafish are a good complement to cell models and mice for ongoing testing of several drug classes involving TLR4 outcomes.
In an era where we often focus on how much humans are different from other species; we tend to forget about the cellular similarities between them. By discovering novel ligands for TLR4 in zebrafish, their work highlights a shared immunological response that allows us to use this model to expand the knowledge of metal-induced allergies in an accessible way.