Scientists solve 30-year-old mystery and discover a hidden defense against inflammation
Scientists have solved a decades-old mystery and uncovered a hidden immune system defense that protects healthy cells from the very inflammation meant to fight infections. The surprising discovery could lead to new approaches for treating cancer, inflammatory bowel disease, and other conditions involving excessive inflammation.
Key points
- Researchers at Memorial Sloan Kettering identified DHRS7 as the gene behind an enzyme that puzzled scientists since 1992.
- Zebrafish, not mice, were used because mice lack a receptor for the 5-oxoETE signal.
- Blocking the pathway worsened inflammation, showing the signal also shields healthy tissue.
Scientists at Memorial Sloan Kettering Cancer Center (MSK) have identified a human gene that produces an enzyme first observed in 1992 but never linked to its genetic source, solving a mystery that stood for more than three decades. The findings were published October 7 in Nature.
The enzyme is involved in signaling by 5-oxoETE, a fatty molecule that attracts immune cells to infection sites. The team found the pathway does more than call immune cells into action: it also protects healthy tissue from the chemicals those cells release.
Why zebrafish instead of mice
Mice and rats are the standard animal models in biomedical research, but they lack a known receptor that recognizes 5-oxoETE, so the full pathway cannot be studied in them. Zebrafish have kept the necessary machinery.
Postdoctoral researcher Yanan Ma, working in Philipp Niethammer's lab, switched off candidate genes in cultured human cells and found that disabling DHRS7 stopped the enzyme from working. Tests with the rodent version of the gene showed almost no enzyme activity.
As it turns out, this signal isn't just an alarm, it's also a shield.
— Dr. Philipp Niethammer
Removing the signal worsened inflammation
Postdoctoral researcher Miklos Lengyel was separately studying colitis in zebrafish. Removing the receptor gene hcar1-4, or later DHRS7, caused intestinal inflammation even without infection, the opposite of what the team expected.
The researchers traced the protection to NUDIX hydrolases, enzymes that clear damaged DNA building blocks. Without the pathway, gut cells could not withstand chemical stress from ordinary gut bacteria, and some died.
The pathway is known to be disrupted in cancer, inflammatory bowel disease and asthma, and mutations in DHRS7 and OXER1 have been found in tumors of the gastrointestinal tract and uterus. Lengyel said more research is needed but activating the pathway might one day help protect the gut from damage caused by radiation or chemotherapy.
