Science: Revealing the Devil Behind the Death Killer

A new study has found that interleukin-3 (IL-3), an inflammatory factor closely associated with anaphylaxis, seems to play an important role in life-threatening immune response sepsis.

In the March 13 issue of Science, researchers from the Massachusetts General Hospital (MGH) described their findings that the presence of IL-3 in a septic mouse model is a necessary condition for sepsis, and the higher the level of IL-3 in human sepsis patients, the higher the risk of death.

"Septicemia is an extremely dangerous disease that kills up to 500,000 people in the United States every year and millions around the world. Our study confirms that in response to infection, IL-3 promotes the production of inflammatory monocytes and neutrophils, which are the source of so-called "cytokine storms" at the root of sepsis. said by r Filip Swirski, senior author of the study and the Center for Systems Biology, Massachusetts General Hospital.

Septicemia occurs when the immune system overreacts to infection or injury and produces excessively high levels of cytokines to attract immune cells. Elevated levels of these cells produce more cytokines, a cytokine storm that recruits more immune cells, leading to a vicious cycle. Immune factors do not stop the initial infection, but attack the tissues and organs of the body, leading to organ failure and death.

At present, little is known about the underlying mechanism of this sepsis, because IL-3 promotes the production and proliferation of several types of white blood cells, some of which produce cytokine storm-related factors. Swirskis team investigated its potential impact on sepsis.

They first demonstrated in a septicemic mouse model that lack of IL-3 prevents sepsis and reduces the production of immune cells and cytokines associated with sepsis. They also found that injecting IL-3 into mice whose expression of this factor was knocked out could restore the susceptibility of mice to sepsis, prevent the interaction between IL-3 and receptors on immune cells, and reduce the production of sepsis-related factors.

Searching for the source of sepsis-induced IL-3 revealed that it was generated by B cells in the spleen, thymus and lymph nodes, which were confirmed to be IRA B cells first discovered by Swirskis team in a 2012 Science paper. These cells also produce growth factor GM-CSF; without IRA B cell-derived GM-CSF, septicemia-inducing animals die faster and more frequently than control animals. However, although GM-CSF resisted sepsis in earlier studies, IL-3 produced by the same cell population in current studies promoted the production of some inflammatory cytokines and aggravated sepsis, reflecting the delicate balance of immune responses: both resistance to infection and avoidance of damage that led to sepsis.

To confirm that the results observed in the mouse model reflect events in human patients, the researchers analyzed blood samples from 60 septicemic patients in a previous study and found that IL-3 levels were higher within 24 hours of the onset of septicemia in patients who eventually died. In another group of 37 patients treated with sepsis, the researchers measured levels of IL-3 and monocytes in advance, and found that the incidence of sepsis was accompanied by a rapid increase in cytokine levels, and the patients with the highest levels of IL-3 were most likely to die.

There are some doubts about the extent to which septicemia mouse models reflect human diseases. Our research shows that the role of IL-3 found in mice is also very important for human patients. Because some seemingly healthy people also have a certain level of IL-3 in their blood, it is important to investigate whether those with high levels of IL-3 have a higher risk of sepsis and other infectious complications, and whether targeting IL-3 and its signaling pathways is a treatment for sepsis. Overall, we need to better understand the role of IL-3 in sepsis and other infectious and non-communicable diseases. We are currently investigating whether IL-3 is involved in the inhibitory phase of sepsis, which occurs after the initial inflammatory phase and puts patients at risk of secondary infection. said by Swirski.

 

Cindy