Mouse Study Links Immune Receptor EP2 to Widespread Aging Changes
Stanford researchers found that removing or blocking the EP2 receptor in tissue-resident macrophages improved inflammation, physical performance, memory-related tests and several organ measures in older mice. Similar patterns involving neutrophils and EP2 activity appeared in human liver-cell data, but no human treatment trial has established that blocking the receptor slows aging in people.
A Stanford Medicine study in mice has identified the immune-cell receptor EP2 as a possible contributor to age-related inflammation and declining organ function. Removing the receptor from tissue-resident macrophages helped older mice retain several characteristics associated with younger animals, including lower inflammation, greater muscle strength and better performance on memory-related tests.
The findings, published in Science, focus on the relationship between two types of immune cells. Neutrophils are short-lived white blood cells that help respond to infection, while macrophages remove dead, damaged or dysfunctional cells. As mice age, more neutrophils become senescent—a dysfunctional state in which they can release substances that promote inflammation. The study reports that tissue-resident macrophages also become less effective at clearing these cells.
The researchers linked that decline to prostaglandin E2, or PGE2, an inflammatory hormone whose levels increase with age. PGE2 activates several receptors, including EP2, which is found in high concentrations on tissue-resident macrophages. In the study, repeated EP2 stimulation weakened the macrophages’ ability to engulf and digest worn-out neutrophils, allowing more of them to accumulate in tissues and the bloodstream.
To test the receptor’s role, the team engineered mice so EP2 could be deleted specifically in tissue-resident macrophages. Older mice lacking the receptor had lower levels of senescent neutrophils in the liver, spleen and bone marrow, along with smaller increases in other organs examined. They also had less visceral fat, more muscle and stronger performance on tests of speed, balance and forelimb grip. Their results on maze navigation and object-recognition tasks were closer to those of younger mice than to untreated older mice.
The effects extended across several biological measures. In older control mice, 71 blood proteins changed significantly compared with younger animals; 59 of those proteins remained at youthful levels in older mice without macrophage EP2. The researchers also reported reduced inflammation in the blood, liver, colon, heart, kidney and hippocampus.
A separate experiment gave an experimental EP2-blocking drug to otherwise normal 22-month-old mice for two months. The treatment moved total and senescent neutrophil levels closer to those seen in younger animals. Cell-culture experiments likewise showed that EP2 blockade restored some age-related loss of macrophage cleanup ability.
The study also examined a database of young, old and diseased human liver cells. Older human liver samples showed patterns resembling the mouse findings, including more neutrophil accumulation and senescence, reduced tissue-resident macrophage function and higher EP2 activity. These observations came from human cell data, not a clinical trial.
No approved drug that selectively blocks EP2 is currently available, according to the report. Broadly reducing PGE2 may also interfere with other prostaglandin functions, including potentially beneficial effects. The researchers therefore described development of a selective and safe EP2 inhibitor as a future goal. The current evidence remains preclinical, and the mouse results do not establish that EP2 blockade will slow aging or improve health in humans.
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