Sepsis is a life-threatening condition caused by the body’s overreaction to infection, causing 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 “sep,” meaning “decay.”
Despite dramatic improvements in the understanding of the immunological mechanisms underlying sepsis, it remains a major medical problem, affecting 750,000 people in the United States and nearly 50 million people worldwide each year. Sepsis killed 11 million people worldwide in 2017 and is the costliest disease in the United States, costing more than tens of billions of dollars annually.
We are scientists 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 outcomes such as sepsis. In a recently published study, we discovered the cells and molecules that can cause death from sepsis.
TNF in autoimmunity and sepsis
The body’s response to infection begins when immune cells recognize components of an 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 important 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 rejection caused by transplant complications.
They can also occur with viral infections, including COVID-19. This uncontrolled immune response can lead to multiple organ failures and death.
Among the hundreds of cytokines that exist, tumor necrosis factor, or TNF, is the most effective and has been the most studied for almost the past 50 years.
Tumor necrosis factor is named for its ability to cause tumor cell death when the immune system is stimulated by a bacterial extract called Coley toxin, named after the scientist who identified it more than a century ago. This toxin was later identified as lipopolysaccharide, or LPS, a component of the outer membrane of certain types of bacteria. LPS is the strongest known TNF trigger, which helps to carefully recruit immune cells to eliminate invading bacteria at the site of infection.
Under normal conditions, TNF promotes beneficial processes such as cell survival and tissue regeneration. However, TNF production must be tightly regulated to prevent continued inflammation and the proliferation of immune cells. Uncontrolled TNF production can lead to the development of rheumatoid arthritis and similar inflammatory conditions.
In infectious conditions, TNF must also be tightly regulated to prevent excessive tissue and organ damage from inflammation and an overactive immune response. If 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 causes immune cells to over proliferate, recruit, and die, ultimately leading to tissue and organ damage. Too strong an immune response is not good.
Researchers have shown that blocking TNF activity can effectively treat many autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease. TNF blockers have grown in popularity in recent decades, with a market value of approximately $ 40 billion.
TNF blockers, however, failed to prevent the cytokine storm that can occur due to COVID-19 infections and sepsis. This is partly because how TNF triggers its toxic effects in the body is still poorly understood despite years of research.
How TNF Can Be Lethal
Studying sepsis can provide clues about how TNF mediates the immune system’s response to infection. In acute inflammatory conditions such as sepsis, TNF blockers fail to reduce TNF overproduction. However, studies in mice show that neutralizing TNF can prevent animal death from bacterial LPS. Although researchers do not yet understand the reason for this difference, it highlights the need to better understand how TNF affects sepsis.
Blood cells, or myeloid cells born in the bone marrow, are known as the most important producers of TNF. Thus, we wondered whether myeloid cells also mediate TNF-induced death.
First, we identified which specific molecules may provide protection against TNF-induced death. When we injected mice with a lethal dose of TNF, we found that mice lacking TRIF or CD1
Survival was improved by two proteins that are normally involved in the immune response to bacterial LPS but not TNF.This finding is consistent with our previous work, which identified these factors as regulators of a protein complex that regulates 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 myeloid cell types, 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 CD1are potential therapeutic targets in sepsis that can reduce both cell death and inflammation.
