UF researchers discover iron plays key role in immune system health

Dr. Liang Zhou in his laboratory.

Dr. Liang Zhou in his laboratory at the UF College of Veterinary Medicine.

By Sarah Carey

Most people know that iron is important for producing healthy red blood cells and that the lack of iron can cause anemia, but University of Florida researchers have discovered that iron plays another key role: It regulates the immune system, especially in the intestine.

For years, iron deficiency was considered a consequence of inflammatory bowel disease, or IBD, which affects one in every 100 Americans, resulting from chronic blood loss and impaired iron absorption. However, this discovery by UF scientists, reported in Nature Immunology, suggests that iron deficiency may contribute to the development of IBD and other immunological disorders.

Iron is taken into the immune cells in the gut by a protein known as transferrin receptor, or CD71, said Liang Zhou, M.D., Ph.D., a professor of immunology in the UF College of Veterinary Medicine and the study’s corresponding author. His research has focused on mucosal immunology at length, and on ILC3s — rare immune cells in the gut that are key to human health.

“Now we’ve found that iron actually regulates these cells, impacting our gut immune responses during infections,” Zhou said.

Iron has an underappreciated role in the regulation of ILC3s, but Zhou’s findings, while seemingly surprising, made sense, he said.

“This relationship could explain why we have that weakened immune response with anemia,” Zhou said. “People who are anemic don’t deal with infection well. There is a possible reason; these immune cells in the gut, these ILC3s, are compromised due to a lack of iron.”

The group’s findings shed light on why there are many ways iron acts within the body, with broad implications for nutrition and immunity, Zhou added.

“We were trying to understand a seemingly fundamental accepted concept. You might think, ‘Oh, yeah, iron is important.’ But you don’t ask, why or how,” he said.

ILC3 cells have been implicated in cancer, metabolic diseases and infections. Zhou said researchers are increasingly excited about these cells and how they are regulated.

“These new findings really help us understand that these cells are actually modulated by nutritional factors, such as by the essential metal iron,” Zhou said. “Understanding how the environment, both dietary and within the gut microbiome, impacts our immune cells is a future direction in our field.”

Over more than a decade, Zhou’s research, funded by the National Institutes of Health, has focused on the environmental impact on the mucosal immunity. His lab explored how tryptophan metabolites, such as those found in vegetables and microbiome, modulate various cellular pathways by activating the aryl hydrocarbon receptor, or AHR, an environmental sensor. His research team was among the first to identify AHR is a key regulator of ILC3s in the gut. The lab recently earned another competitive renewal of an NIH grant to continue its work with a new focus on iron and ILC3s through AHR and CD71.

“I think what’s really interesting is this AHR/CD71/iron axis,” Zhou said. The axis intrigues his team due to the positive and negative regulation that takes place there, with the net result that the relationship keeps our key immune cells, the ILC3s, in healthy condition.

“Our goal is to modulate this axis to keep our immune system stable and able to fight various diseases and infections when needed,” he said. “Our immune system has very smartly evolved in a way that if one mechanism fails, we have another mechanism to rescue it.”

Zhou doesn’t recommend that healthy people take more iron, but he has a warning for those who don’t get enough of it.

“If for any reason you do not have enough iron in your body, you need to watch out,” he said.

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September-October 2023

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