Decades-Old Mystery Solved: Immune Signal Protects Tissue

Researchers have resolved a biological mystery that has confounded scientists for more than three decades. The discovery reveals an unexpected mechanism within the immune system designed to shield body tissues from collateral damage caused by inflammatory responses. This finding could open new therapeutic avenues for treating cancer, inflammatory bowel disease, and asthma.

The 1992 Enigma and Genetic Breakthrough

The story begins in 1992, when researchers at McGill University identified a lipid molecule known as "5-oxoETE." This compound plays a critical role in directing immune cells toward sites of infection and inflammation. At the time, scientists observed an enzyme capable of both producing and breaking down this molecule but failed to identify the human gene responsible for its synthesis. This gap hindered the understanding of the molecule’s biological functions and its potential links to disease.

For over 30 years, the genetic identity of this enzyme remained unknown. Yanan Ma, a researcher at the Memorial Sloan Kettering Cancer Center (MSK) in the United States, finally pinpointed the gene as "DHRS7." Her work built upon previous research conducted by her former colleague King Lam Hui. The broader investigation is led by cellular biologist Philip Nathans, whose lab focuses on how cells respond to injury, infection, and stress, as well as the role of inflammation in tissue repair and regeneration.

Zebrafish Model Overcomes Rodent Limitations

To achieve this breakthrough, the team adopted an unconventional experimental approach, utilizing zebrafish instead of the mice and rats typically employed in medical trials due to their high genetic similarity to humans. Ma explained that while rodent genomes share approximately 80% similarity with human genes, these animals lack a specific immune receptor capable of recognizing "5-oxoETE." Consequently, rodents are unsuitable models for studying the entire biological pathway.

In contrast, zebrafish retain the necessary components of this system, allowing researchers to observe chemical signaling within a living organism and uncover previously unknown functions. To verify the enzyme's identity, the scientists conducted experiments on cultured human cells. They systematically disabled candidate genes until they discovered that halting "DHRS7" ceased the enzyme's activity, confirming it as the producer. Additional tests showed that the rodent version of the enzyme possessed almost no enzymatic activity, consistent with the absence of the required receptor.

Unexpected Inflammatory Response Mechanism

While Ma searched for the elusive enzyme, researcher Miklos Lengyel was conducting separate experiments on zebrafish to study colitis and understand the genes controlling inflammatory responses. During one trial, Lengyel disabled a gene called "hcar1-4," which is the zebrafish equivalent of the human "OXER1" gene. OXER1 produces the receptor that recognizes "5-oxoETE."

Scientists anticipated that disabling this receptor would reduce inflammation, given the molecule's role in recruiting immune cells to infection sites. However, the results were counterintuitive: the fish developed intestinal inflammation despite the absence of any infection. Researchers initially found no direct explanation until they removed neutrophils—immune cells responsible for attacking microbes—and observed that inflammation persisted.

The surprise deepened when the team disabled the "DHRS7" gene itself. The outcome mirrored the previous experiment: inflammation levels rose rather than fell. The group realized that this biological pathway does not merely activate immune responses; it performs a distinct function by protecting healthy tissue.

Cellular Defense Against Chemical Stress

Experiments demonstrated that immune cells release highly reactive chemicals to combat bacteria and microbes. If the response becomes uncontrolled, these substances can damage surrounding healthy cells at the site of infection. The "5-oxoETE" pathway acts protectively here, helping tissues withstand chemical stress and limiting damage resulting from immune activity.

This protection involves a group of enzymes known as "NUDIX hydrolases." These enzymes maintain cell integrity by eliminating damaged DNA building blocks before they interfere with normal biological processes. When the protective pathway fails, intestinal cells become vulnerable to chemical stress-induced damage. Even natural bacteria residing in the gut can generate low levels of this stress, sufficient to cause harm. This damage leads to cell death, triggering an inflammatory response even without an invading pathogen.

Nathans stated that the detected signal is not just an alarm for summoning immune cells but also serves as a shield, protecting healthy tissues from the materials these cells use to fight pathogens.

Clinical Implications for Cancer and Asthma

The discovery may significantly impact the understanding of diseases linked to inflammation, particularly cancer, inflammatory bowel disease, and asthma. Previous studies have identified mutations in the "DHRS7" and "OXER1" genes within gastrointestinal and uterine tumors. Mutations that disable OXER1 function have been associated with poorer health outcomes in patients with colon, pancreatic, and kidney cancers.

Researchers suggest that activating this pathway in the future could help healthy tissues resist oxidative stress, potentially reducing intestinal damage caused by radiation or chemotherapy. Lengyel noted that enhancing the pathway's activity might increase the intestine's tolerance to oxidative stress, though further research is required before clinical applications emerge.

Findings also highlight the pathway's importance in protecting mucous membranes lining the intestines and respiratory tract. In patients with inflammatory bowel disease, lower levels of "5-oxoETE" in tissues correlated with worse disease outcomes. A separate study on primates showed that disabling the OXER1 receptor weakened some immune cell responses but also eliminated protective mucus-producing cells in the airways.

Mechanical Injury and Integrated Stress Responses

The research extends beyond infection and chemical stress to examine how the pathway responds to physical injuries. PhD student Zaza Gelashvili is investigating the role of mechanical forces generated by tissue damage. These forces can alter cell membranes and trigger the release of arachidonic acid, a lipid molecule that serves as a precursor for "5-oxoETE" production.

Evidence indicates that physical stress initiates a chain of reactions, while oxidative stress contributes to converting chemicals, and the "DHRS7" enzyme amplifies the resulting signal. Researchers believe the body integrates various types of stress—mechanical and chemical—to launch a coordinated response that helps confront danger while simultaneously protecting tissues.

Despite the significance of the discovery, scientists emphasize that translating these findings into human treatments requires additional studies. Understanding the dual role of inflammatory signals could eventually aid in developing drugs that do not merely suppress inflammation but also preserve the body's natural protective mechanisms.