New sepsis research sheds light on how it can lead to cell death

New sepsis research sheds light on how it can lead to cell death

Sepsis is a life-threatening condition resulting from the body’s overreaction to infection that results in damage to its own tissues and organs.

The first known mention of “sepsis” dates back more than 2,700 years ago, when the Greek poet Homer used it as a derivative of the word “sepo,” meaning “to putrefy.” Despite dramatic improvements in the understanding of the immunological mechanisms behind sepsis, it still remains a major medical problem, affecting 750,000 people in the US and nearly 50 million people worldwide each year.

Sepsis was responsible for 11 million deaths worldwide in 2017 and is the most expensive medical condition in the US, costing over tens of billions of dollars annually.

We are researchers who study how certain types of bacteria interact with cells during infections. We wanted to understand exactly how an overreactive immune response can lead to harmful and even fatal effects such as sepsis. In our newly published research, we discovered the cells and molecules that potentially trigger death in 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 eliminate the infection. Cytokines are a broad group of small proteins that recruit other immune cells to the site of infection or injury.

While cytokines play a vital role in the immune response, excessive and uncontrolled cytokine production can lead to the dangerous cytokine storm associated with sepsis.

Cytokine storms were first seen in the context of graft-versus-host disease arising from transplant complications. They can also occur during viral infections, including COVID-19. This uncontrolled immune response can lead to multi-organ failure and death.

Among the hundreds of cytokines in existence, tumor necrosis factor, or TNF, is the most potent and the most studied over the past nearly 50 years.

Tumor necrosis factor owes its name to its ability to induce the death of tumor cells when the immune system is stimulated by a bacterial extract called Coley’s toxin, named after the researcher who identified it more than a century ago.

This toxin was later recognized as lipopolysaccharide or LPS, part of the outer membrane of certain types of bacteria. LPS is the most potent TNF trigger known, which, once on alert, helps recruit immune cells to the site of infection to eliminate the 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 persistent inflammation and continuous proliferation of immune cells. Uncontrolled production of TNF can lead to the development of rheumatoid arthritis and similar inflammatory conditions.

In infectious states, TNF must also be tightly regulated to prevent excessive tissue and organ damage from inflammation and a hyperactive immune response. When TNF is left unchecked during infections, it can lead to sepsis.

For several decades, studies of septic shock have been modeled by examining responses to bacterial LPS. In this model, LPS activates certain immune cells that trigger the production of inflammatory cytokines, especially TNF. This then leads to immune cell overproliferation, recruitment and death, ultimately leading to tissue and organ damage. An overly strong immune response is not a good thing.

Researchers have shown that blocking TNF activity can effectively treat a number of 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 occur as a result of COVID-19 infections and sepsis. This is in part because, despite years of research, exactly how TNF triggers its toxic effects on the body is still poorly understood.

How TNF can be deadly

Studying sepsis may provide some clues as to how TNF mediates how the immune system responds to infection. In acute inflammatory conditions such as sepsis, TNF blockers are less able to address TNF overproduction. However, mouse studies show that neutralizing TNF can prevent the animal from dying from bacterial LPS. Although researchers do not yet understand the reason for this discrepancy, it highlights the need for further understanding of how TNF contributes to sepsis.

Blood cells formed in the bone marrow, or myeloid cells, are known to be the main producers of TNF. We therefore wondered whether myeloid cells also mediate TNF-induced death.

We first identified which specific molecules might offer protection against TNF-induced death. When we injected mice with a lethal dose of TNF, we found that mice lacking either TRIF or CD14, two proteins typically associated with immune responses to bacterial LPS, but not TNF, had improved survival.

This finding is consistent with our earlier work identifying 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 lacking two proteins in two specific types of myeloid cells, neutrophils and macrophages, the mice had reduced sepsis symptoms and improved survival. This finding places macrophages and neutrophils as the main triggers of TNF-mediated death in mice.

Our results also suggest that TRIF and CD14 are potential targets for the treatment of sepsis with the ability to reduce cell death and inflammation.

By Alexander (Sasha) Poltorak and Hayley Muendlein, Tufts University (Interview)

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