Sepsis is a life-threatening condition that arises from the body’s overreaction to an infection, leading to damage to its own tissues and organs. The first known reference to “sepsis” dates back more than 2,700 years, when the Greek poet Homer used it as a derivative of the word “toad,” meaning “I rot.”
Despite dramatic improvements in understanding the immunological mechanisms behind sepsis, it remains a significant medical concern, affecting 750,000 people in the US and nearly 50 million people worldwide each year. Sepsis accounted for 11 million deaths worldwide in 2017 and is the costliest medical condition in the US, costing more than tens of billions of dollars a year.
We are researchers studying how certain types of bacteria interact with cells during infections. We wanted to understand exactly how an overactive immune response can have detrimental and even fatal effects such as sepsis. In our research, recently published in science immunologywe discovered the cells and molecules that potentially trigger death from sepsis.
TNF in autoimmunity and sepsis
The body’s response to infection begins when immune cells recognize components of the invading pathogen. These cells then release molecules such as cytokines that help clear the infection. Cytokines are a large group of small proteins that recruit other immune cells to the site of infection or injury.
Although cytokines play an essential role in the immune response, excessive and uncontrolled production of cytokines can lead to a dangerous cytokine storm associated with sepsis. Cytokine storms were first observed in the setting of graft-versus-host disease, which arises from transplant complications. They can also occur during viral infections, including COVID-19. This uncontrolled immune response can lead to multiple organ failure and death.
Among the hundreds of cytokines that exist, tumor necrosis factor, or TNF, stands out as the most potent and the most studied for almost the last 50 years.
Tumor necrosis factor gets its name from its ability to induce tumor cell death when the immune system is stimulated by a bacterial extract called Coley’s toxin, after the researcher who identified it more than a century ago. This toxin was later recognized to be lipopolysaccharide, or LPS, a component of the outer membrane of certain types of bacteria. LPS is the strongest known activator of TNF, which, once on alert, aids in the recruitment of immune cells to the site of infection to eliminate invading bacteria.
Under normal conditions, TNF promotes beneficial processes such as cell survival and tissue regeneration. However, TNF production must be tightly regulated to prevent sustained inflammation and continued proliferation of immune cells. Uncontrolled production of TNF can lead to the development of rheumatoid arthritis and similar inflammatory conditions.
Under conditions of infection, TNF must also be tightly regulated to prevent excessive tissue and organ damage due to inflammation and an overactive immune response. When TNF is not controlled during infections, it can lead to sepsis. For several decades, septic shock studies have been modeled by investigating responses to bacterial LPS. In this model, LPS activates certain immune cells that trigger the production of inflammatory cytokines, particularly TNF. This leads to excessive proliferation, recruitment, and death of immune cells, ultimately resulting in tissue and organ damage. Too strong an immune response is not a good thing.
Researchers have shown that blocking TNF activity can effectively treat numerous autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease. The use of TNF blockers has increased dramatically in recent decades, reaching a market size of approximately $40 billion.
However, TNF blockers have not been successful in preventing the cytokine storm that can arise from COVID-19 infections and sepsis. This is partly because, despite years of research, exactly how TNF triggers its toxic effects in the body is still not understood.
How TNF can be lethal
The sepsis study could provide some clues about how TNF mediates the way the immune system responds to infection. In acute inflammatory conditions such as sepsis, TNF blockers are less able to address TNF overproduction. However, studies in mice show that neutralizing TNF can prevent death of the animal from bacterial LPS. Although researchers do not yet understand the reason for this discrepancy, it highlights the need to better understand how TNF contributes to sepsis.
Blood cells produced in the bone marrow, or myeloid cells, are known to be the main producers of TNF. So we wonder if myeloid cells also mediate TNF-induced death.
First, we identified which particular molecules might offer protection against TNF-induced death. When we injected mice with a lethal dose of TNF, we found that mice lacking TRIF or CD14, two proteins typically associated with immune responses to bacterial LPS but not TNF, had improved survival. This finding parallels our previous work that identified these factors as regulators of a protein complex that controls cell death and inflammation in response to LPS.
Next, we wanted to find out which cells are involved in TNF-induced death. When we injected a lethal dose of TNF into mice that lacked the two proteins in two specific types of myeloid cells, neutrophils and macrophages, the mice had reduced sepsis symptoms and improved survival. This finding positions macrophages and neutrophils as the main triggers of TNF-mediated death in mice.
Our results also suggest that TRIF and CD14 are potential treatment targets for sepsis, with the ability to reduce cell death and inflammation.
Hayley I. Muendlein et al, Neutrophils and macrophages drive TNF-induced lethality through TRIF/CD14-mediated responses, science immunology (2022). DOI: 10.1126/sciimmunol.add0665
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