Scientists Solve 30-Year-Old Immune System Mystery, Discover How Body Prevents Inflammation Damage

Scientists have uncovered a previously unknown mechanism through which the immune system protects healthy tissue from damage caused by its own inflammatory response, solving a biological mystery that has puzzled researchers for more than three decades. The discovery could open new avenues for treating conditions such as cancer, inflammatory bowel disease and asthma.

The breakthrough, led by researchers at Memorial Sloan Kettering Cancer Center (MSK), reveals that a chemical signal used to recruit immune cells to fight infections also plays a role in controlling inflammation and preventing excessive tissue damage.

The findings, published in the journal Nature on October 7, identify a long-mysterious enzyme and explain how it contributes to this protective process. The researchers used zebrafish rather than the more commonly studied mice to investigate the biological pathway, an approach that proved crucial to uncovering the mechanism.

The discovery could help scientists develop treatments that reinforce the body’s natural ability to limit inflammatory damage while maintaining its defences against infections.

A Scientific Mystery That Began in 1992

The research addresses a question that dates back to 1992, when scientists at McGill University first investigated a fatty signalling molecule called 5-oxoETE, or 5-oxo-6,8,11,14-eicosatetraenoic acid.

The molecule acts as a chemical messenger, guiding immune cells towards areas where infections or other threats are present. During their investigation, researchers identified an enzyme capable of both producing and breaking down 5-oxoETE. However, they could not establish which human gene was responsible for producing it.

Without identifying the gene, scientists had limited opportunities to manipulate the enzyme, study its biological functions or understand how changes in its activity might influence disease. Although researchers gave the enzyme a descriptive name based on its chemical role, its genetic identity remained unresolved for over 30 years.

That changed when Yanan Ma, PhD, a postdoctoral researcher at MSK’s Sloan Kettering Institute, identified the human gene responsible for producing the enzyme. Her work built on earlier investigations by her former laboratory colleague King Lam Hui, PhD.

The identification gave scientists a way to investigate the enzyme’s activity and its contribution to the body’s inflammatory response.

How the Immune System’s Defences Can Harm Healthy Tissue

The immune system relies on inflammation to identify and eliminate harmful microorganisms. When bacteria enter the body, chemical messengers attract specialised white blood cells to the infected area, where they release substances that attack and destroy the invading pathogens.

One of the chemical signals involved in this process is 5-oxoETE, which helps direct immune cells towards the site of infection.

However, inflammation is not always beneficial. The same substances that help immune cells eliminate bacteria can also damage nearby healthy cells when the response becomes excessive.

“They flood the site with toxic substances to kill the bacteria,” Dr. Niethammer says. “But this can cause damage to healthy cells if it gets out of control.”

This balance between fighting infections and protecting healthy tissue is central to the research conducted by Philipp Niethammer, PhD, a cell biologist whose laboratory investigates how cells respond to injuries, infections and other forms of stress.

His team studies inflammation, tissue repair and regeneration, processes that are also closely connected to cancer and several other diseases.

Researchers in Niethammer’s laboratory had spent years examining the molecular mechanisms involved in 5-oxoETE signalling. However, the unidentified enzyme remained a significant gap in their understanding of how the pathway operates.

Why Researchers Turned to Zebrafish Instead of Mice

One of the most important aspects of the investigation was the choice of animal model. Mice and rats are widely used in biomedical research because their genetic makeup shares considerable similarities with that of humans.

However, these rodents lack a known immune cell receptor that can recognise 5-oxoETE. This makes them unsuitable for investigating the complete signalling pathway.

Zebrafish, on the other hand, retain the biological components required for this process, allowing researchers to study the pathway in a living organism.

“Mice and rats are the primary model used in biomedical research,” says Dr. Ma, who received a prestigious Marie-Josée Kravis WISE Fellowship in 2023 for her research on the pathway. “It makes sense — they’re mammals, and there’s about an 80% overlap between their genes and ours.”

Despite the genetic similarities between humans and rodents, the missing receptor presented a major limitation for this particular investigation.

“This means that you can’t study the pathway in mice,” Dr. Ma says. “But the pathway is intact in fish. So picking the right alternative model was critical to advancing our understanding of how the human body responds.”

By choosing zebrafish, the researchers could examine the signalling system under conditions that conventional rodent models could not adequately reproduce. This ultimately helped them uncover the protective role associated with the enzyme.

Researchers Identify DHRS7 as the Missing Gene

To determine the enzyme’s genetic origins, Ma and Hui initially worked with cultured human cells. They shortlisted several potential genes and systematically switched them off to observe whether doing so affected the enzyme’s activity.

One candidate produced a clear result. When researchers disabled a gene known as DHRS7, the enzyme stopped functioning.

This established DHRS7 as the gene responsible for producing the enzyme that scientists had been unable to identify since 1992.

The team also examined the corresponding gene in rodents and found almost no enzyme activity. This finding was consistent with the absence of the 5-oxoETE receptor in mice, indicating that rodents had lost important components of this signalling system.

Identifying DHRS7 finally resolved the decades-old question and provided researchers with an opportunity to investigate the pathway in greater detail.

The discovery also brought together two separate research projects conducted within Niethammer’s laboratory. While Ma and Hui were investigating the unidentified enzyme, another postdoctoral researcher, Miklos Lengyel, MD, PhD, was leading a separate investigation that contributed to the broader findings.

Dr. Niethammer highlighted the unusual collaboration and the importance of bringing the two projects together.

“Typically, when you have a paper with two first authors like Yanan and Miklos, there is just one story that two people contributed to equally,” Dr. Niethammer says. “But this paper is not like that. In this paper, there are two separate projects led by two different authors that came together as one larger discovery. And I think that’s extremely important to note.”

What the Discovery Could Mean for Future Treatments

The findings offer scientists a better understanding of how the immune system regulates inflammation and protects the body from collateral damage during an infection.

By identifying DHRS7 and examining the biological pathway associated with 5-oxoETE, researchers now have a clearer picture of a mechanism that had remained poorly understood for decades.

The discovery could prove particularly relevant to diseases in which inflammation plays a significant role, including cancer, inflammatory bowel disease and asthma.

It also provides a potential starting point for developing therapies that strengthen the body’s natural mechanisms for controlling inflammatory damage.