Dying cells trigger a fatal cascade in sepsis

Dying cells trigger a fatal cascade in sepsis

Like a poison pen, dying cells prick their neighbors with a deadly message. This can worsen sepsis, Vijay Rathinam and colleagues report in the UConn School of Medicine report in the Jan. 23 issuecell. Their findings could lead to a new understanding of this dangerous disease.

Sepsis is one of the leading causes of death worldwide, killing 11 million people each year, according to the World Health Organization (WHO). It is characterized by out-of-control inflammation, usually triggered by an infection. It can lead to shock, multiple organ failure, and death if treatment is not fast enough or effective.

However, recent research has shown that it is not the infection that causes spiral inflammation: it is the cells trapped in it. Even if these cells are not infected, they act as if they are and die. As they die, they send messages to other cells. These messages somehow cause the recipient cells to die. Once scientists understand what caused this deadly chain of messages, they may be able to stop it. And that could help cure sepsis.

The deadly embassy mystery can now be solved. It appears that the "messages" are a byproduct of cells trying to stay alive, researchers at the UConn School of Medicine reportcell.

The process begins with cells that are truly infected. To prevent the infection from spreading, these cells destroy themselves by sending a protein called Gadermin-D to their surface. Multiple Gadermin D proteins combine together to create a round pore in the cell, like a hole punched in a balloon. The contents of the cell leak, the cell collapses and dies.

But collapse is not inevitable. Sometimes cells can act quickly and eject the portion of their surface membrane containing the Gadermin-D pore. The cell then tears off the membrane and survives. The expelled membrane forms a small bubble called a vesicle, which happens to carry the deadly Gasdermin-D pore. The vesicle floats around, and when it encounters a nearby cell, this deadly Gadermin-D pore strikes the healthy cell's membrane of the nearby cell, causing that cell to spill and die.

When a dying cell releases these vesicles, they can transplant these pores onto the surface of a neighboring cell, resulting in the death of the neighboring cell. “

Vijay Rathinam, an immunologist at the UConn School of Medicine

In other words, the deadly messages are a side effect of cells just trying to save themselves. A group of dying cells can release enough Gadermin-D vesicles to kill a significant number of nearby cells. This widespread message of death drives the spiral inflammation of sepsis.

Rathinam and his colleagues are now looking for a way to dampen the deadly Gadermin-D vesicles. If successful, it could lead to treatment for inflammatory diseases such as sepsis.

This study, led by Skylar Wright, an MD/PhD student in the Rathinam laboratory, was conducted in collaboration with DRS laboratories. Jianbin Ruan, Beiyan Zhou, Sivapriya Kailasan Vanaja from UConn Health and Dr. Katia Cosentino from the University of Osnabrück, Germany. This project was supported by a grant from the National Institutes of Health to Dr. Rathinam financed.

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