Sepsis: Studying sepsis may provide some clues as to how TNF mediates how the immune system responds to infection.
The Conversation: sepsis It is a life-threatening disease that results from the body’s response against an infection in which it starts damaging its own tissues and organs. The first reference to “sepsis” dates back 2,700 years, when the Greek poet Homer used it as the word “sepo,” meaning “I am rotting.” Despite great improvements in the understanding of the immunological mechanisms of sepsis over time, it still remains a concern, affecting 750,000 people in the US and approximately 50 million people worldwide each year.
In 2017, 11 million people died of sepsis worldwide. Its condition is serious in America, which costs more than billions of dollars annually.
We are researchers who study how certain types of bacteria interact with cells during infection. We really wanted to understand how an overreactive immune response can cause harmful and fatal effects like sepsis. In our newly published research, we discovered the cells and molecules that potentially trigger death due to sepsis.
TNF in autoimmunity and sepsis
The body’s response against 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 an essential role in the immune response, excessive and uncontrolled cytokine production can lead to the dangerous cytokine storm associated with sepsis.
Cytokine storms were first observed in the context of graft versus host disease, resulting from transplant complications. They can also arise during viral infections including COVID-19. This uncontrolled immune response can lead to multiple organ failure and death.
Of the hundreds of existing cytokines, tumor necrosis factor or TNF is the most potent and has been studied the most over the past 50 years.
Tumor necrosis factor is also present
Tumor necrosis factor gets its name from its ability to induce tumor cells to die when the immune system is stimulated with a bacterial extract called Coley’s toxin, named after the researcher who discovered it over a century ago. had recognized
This toxin was later identified as lipopolysaccharide, or LPS, a component of the outer membrane of certain types of bacteria. LPS is the strongest trigger of TNF, which, once alerted, aids in the recruitment of immune cells to the site of infection to eliminate the invading bacteria.
Under normal circumstances, TNF promotes beneficial processes such as cell survival and tissue regeneration. However, to avoid inflammation and the continued proliferation of immune cells, TNF production must be controlled. Uncontrolled TNF production can lead to rheumatoid arthritis and increased inflammation.
In the event of infection, TNF must be up-regulated to prevent tissue and organ damage due to inflammation and an overactive immune response. When TNF is left unchecked during an infection it can lead to sepsis.
what is activity
For decades, the study of septic shock was modeled by examining responses to bacterial LPS. In this model, LPS activates certain immune cells that trigger the production of inflammatory cytokines, in particular TNF. This then leads to excessive proliferation of immune cells, their recruitment and death, ultimately resulting in tissue and organ damage. Too 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 grown rapidly over the past decades, reaching a market size of approximately US$40 billion (billion).
However, TNF blockers have been unsuccessful in stopping the cytokine storm that can result from COVID-19 infection and sepsis. This is because despite years of research, how TNF triggers its toxic effects on the body is not fully resolved.
How TNF can be fatal
Studying sepsis may provide some clues as to how TNF mediates how the immune system responds to infection. In acute inflammatory conditions like sepsis, TNF blockers are not very capable of detecting TNF overproduction. However, studies in mice show that neutralizing TNF can prevent animal death caused by bacterial LPS. Although researchers do not yet understand exactly why, it highlights that we need to understand how TNF contributes to sepsis.
Blood cells made in the bone marrow, or myeloid cells, are known to be the major producers of TNF. We therefore wondered whether myeloid cells also mediate TNF-induced cell death.
First, we identified which specific molecules may confer protection against TNF-induced death. When we injected mice with a lethal dose of TNF, we found that the mice lacked either TRIF or CD14, two proteins typically associated with the immune response to bacterial LPS, but not to TNF. His survival had improved.
This finding is consistent with our earlier finding that 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 lethal doses of TNF into mice that lacked two specific types of myeloid cells, neutrophils and macrophages, the mice experienced reduced sepsis symptoms and improved survival. This finding implicates macrophages and neutrophils as major triggers for TNF-mediated death in mice.
Our results also suggest TRIF and CD14 as potential therapies for sepsis, which have the potential to reduce both cell death and inflammation. (The Conversation)
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