Biologists at Memorial Sloan Kettering Cancer Center in New York have solved a puzzle that had gone unanswered for nearly thirty years: they have discovered a previously unknown protective barrier of the human immune system. According to ScienceDaily, the study showed that a molecular signal that draws white blood cells to the site of an infection simultaneously shields healthy tissue from the destructive effects of its own defensive responses, infohub.kz reports.
The signal in question is a lipid signaling molecule called 5-oxoETE, first described back in 1992 by researchers at McGill University. At the time, an enzyme that both synthesizes and breaks it down was also identified, but the human gene encoding this protein remained unknown for more than three decades. The findings were published in the journal Nature.
The breakthrough came from the lab of cell biologist Philipp Niethammer. Researcher Yanan Ma was able to pinpoint that the human gene DHRS7 is responsible for producing the key enzyme.
The work was completed with the help of zebrafish rather than conventional laboratory mice. In rodents, the cellular receptor for 5-oxoETE disappeared over the course of evolution, whereas in fish this signaling chain has been preserved unchanged. Studying colitis in zebrafish, researcher Miklós Lengyel switched off the hcar1-4 receptor (the human equivalent is OXER1) and the DHRS7 gene. Contrary to expectations, turning off the pro-inflammatory signal did not reduce but sharply intensified intestinal inflammation, even in the complete absence of pathogens.
It turned out that the immune signal activates NUDIX hydrolase enzymes, which remove damaged DNA fragments. Without this protection, cells die from toxic substances released by white blood cells.
The discovery is of key importance for oncology: mutations in DHRS7 and OXER1 are frequently found in tumors of the gastrointestinal tract and uterus, and activating them may protect the intestine from radiation and chemotherapy.