Triggering Receptor Expressed on Myeloid cells 1 (TREM-1) is a protein receptor on the surface of specific immune cells that functions as an amplifier for the body’s inflammatory response. When the body detects an infection or injury, immune cells are activated to begin the defense process. TREM-1 enhances these initial defensive signals, ensuring a rapid mobilization of the immune system to the site of the problem by intensifying communication between these cells.
How TREM-1 Works in the Immune System
TREM-1 is found on the surface of myeloid cells, a major component of the innate immune system. These cells include neutrophils, monocytes, and macrophages, which are among the first to arrive at an infection or tissue damage. Its location on these frontline cells is strategic, allowing it to quickly respond to danger signals.
When myeloid cells detect molecular patterns from pathogens, they initiate an inflammatory response. TREM-1 activation does not start this response but magnifies it. It works with other receptors, like Toll-like receptors (TLRs), to boost the production of pro-inflammatory molecules called cytokines and chemokines. This synergy creates a feedback loop that escalates the immune reaction.
The amplified release of these molecules acts as a chemical alarm, recruiting more immune cells to the threat to contain and eliminate microbes. This mechanism is mediated through an adapter protein called DAP12. Once TREM-1 is engaged, DAP12 initiates a signaling cascade inside the cell, leading to the heightened inflammatory output.
The Role of TREM-1 in Disease
While TREM-1’s amplification power is beneficial for fighting infections, its over-activation can drive disease. An uncontrolled TREM-1 response can lead to a hyperinflammatory state, causing significant damage to the body’s tissues. This is evident in sepsis, a life-threatening condition arising from the body’s overwhelming response to an infection.
In sepsis, bacterial products in the bloodstream trigger massive activation of TREM-1 on neutrophils and monocytes. This leads to a “cytokine storm,” a massive release of inflammatory molecules throughout the body. This flood of cytokines can cause widespread inflammation, blood vessel leakage, a sharp drop in blood pressure, and multiple organ failure.
Beyond acute conditions like sepsis, persistent TREM-1 activation is implicated in chronic inflammatory diseases. In conditions such as inflammatory bowel disease (IBD) and rheumatoid arthritis, ongoing TREM-1 signaling contributes to chronic inflammation and tissue destruction. Researchers have also noted its involvement in atherosclerosis and non-alcoholic fatty liver disease.
TREM-1 as a Biomarker
A portion of the TREM-1 receptor can be cleaved from the cell surface and enter circulation. This soluble form, known as sTREM-1, can be measured in bodily fluids like blood. The presence of sTREM-1 indicates the level of inflammatory activity within the body, making it a useful biomarker.
Elevated levels of sTREM-1 in a patient’s blood correlate with the severity of an inflammatory response. This is useful in diagnosing conditions like sepsis and other severe bacterial or fungal infections. Measuring sTREM-1 helps clinicians distinguish a systemic inflammatory response from conditions with similar symptoms.
sTREM-1 is also used for monitoring a patient’s condition. A rise in sTREM-1 levels may indicate a worsening infection or a failing response to treatment, while a decrease can signal that the inflammation is subsiding. This makes sTREM-1 a dynamic tool for tracking disease progression and the effectiveness of interventions.
Targeting TREM-1 for Therapy
The destructive potential of TREM-1 over-activation makes it an attractive target for therapeutic intervention. The goal is to modulate the immune response, turning down the inflammatory amplification to prevent collateral damage. This has led to the development of drugs designed to block TREM-1 activity.
TREM-1 inhibitors are molecules designed to interfere with the receptor’s signaling process. By binding to TREM-1 or its associated pathways, these inhibitors prevent it from sending its amplification signal. This approach aims to dampen the excessive inflammatory cascade in conditions like septic shock without completely suppressing the immune system’s ability to fight the underlying infection.
The development of TREM-1 inhibitors is an active area of research, with several candidates being investigated in preclinical studies and clinical trials. These efforts focus on creating treatments for patients with hyperinflammatory states to restore balance to the immune response. If successful, these therapies could offer a new way to manage severe inflammatory conditions and improve patient outcomes.