The inflammatory receptor EP2 prevented immune cells from clearing senescent neutrophils and accelerated organ aging in mice
The inflammatory receptor EP2 prevented immune cells from clearing senescent neutrophils and accelerated organ aging in mice
On July 16, a Stanford team published a study in Science showing that EP2 signaling impaired tissue macrophage function in old mice. When the researchers disabled this receptor only in macrophages, the cells resumed clearing senescent neutrophils, while the animals retained heart function, muscle function, memory, and the function of other organs.
Neutrophils are the most abundant and shortest-lived white blood cells. They are the first to attack an infection, but they must then disappear quickly. Tissue macrophages, the resident immune cells of organs, engulf neutrophils and break them down internally. The human body produces more than 100 billion neutrophils each day. Macrophages must continuously clear this mass of cells from the organs.
This process failed with age in mice. Neutrophils showing signs of cellular senescence accumulated in the liver, spleen, bone marrow, and other organs. These cells released damaging enzymes and initiated NETosis, the release of networks made from DNA and proteins that neutrophils use against microbes. Within tissues, these networks and secreted substances exposed neighboring cells to inflammatory stress.
The researchers found the inhibitory mechanism within the macrophages themselves. Prostaglandin E2, a signaling lipid whose levels rise during inflammation, activates the EP2 receptor on the macrophage surface. EP2 blocks the first step of clearance: it reduces the activity of integrins, the proteins that enable cells to attach to their targets. As a result, the macrophage cannot hold the neutrophil effectively or draw it into a phagolysosome, the internal vesicle that breaks down engulfed material. A review of senescent macrophages in vascular plaques previously described the loss of clearance function in one organ. Tan's team identified the molecular brake responsible for this failure across several tissues.
The team genetically disabled EP2 only in tissue macrophages. Neutrophil clearance resumed in old mice, while measures of frailty, muscle loss, obesity, heart function, memory, and inflammation moved closer to those observed in young animals. An experimental EP2 inhibitor given to 22-month-old mice for two months also reduced the number of senescent neutrophils and restored their uptake by macrophages.
One approach to treating aging is to remove senescent cells directly. This study proposes restoring the immune system's ability to clear one particularly abundant class of cells. The researchers observed the same age-related pattern in human liver and heart tissues: more EP2 in macrophages, more senescent neutrophils, and fewer contacts between the two cell types. Translation to humans will require a selective and safe EP2 inhibitor. The current data establish a target and a mechanism, not a ready-to-use drug.