Triggering Receptor Expressed on Myeloid cells 1 (TREM-1) is a protein found on the surface of immune cells, primarily myeloid cells like neutrophils and macrophages. These cells are involved in the body’s initial response to infection and injury. TREM-1 generally amplifies inflammatory responses, acting as an accelerator for the immune system.
TREM-1’s Role in Immune Responses
TREM-1 amplifies inflammatory responses, especially to pathogens and tissue damage. When activated, it works in conjunction with other receptors, such as Toll-like receptors (TLRs), to enhance pro-inflammatory cytokine production (e.g., TNF-α, IL-1β, IL-8). This action helps defend against microbes like bacteria and fungi. TREM-1 signaling begins when a ligand binds to the receptor, triggering the association and phosphorylation of the adaptor protein DAP12. This cascade activates protein tyrosine kinases, leading to phosphorylation of various proteins and activation of downstream signaling pathways, including extracellular signal-regulated kinases (ERK).
While TREM-1 is beneficial for clearing infections and initiating repair processes, its overactivation can lead to harmful, uncontrolled inflammation. In animal models of bacterial infections, blocking TREM-1 signaling has been shown to reduce excessive inflammation and improve survival. Conversely, sustained activation of the TREM-1/DAP12 pathway can increase susceptibility to conditions like LPS-induced shock. This highlights a delicate balance where TREM-1’s activity is necessary for effective immunity, but its dysregulation can contribute to pathological conditions.
TREM-1 is expressed on various myeloid cells, including circulating neutrophils and monocytes/macrophages, and is also found on lung alveolar macrophages, which are specialized in clearing pathogens and cellular debris. Its expression is often upregulated in the presence of bacterial and fungal infections in human skin and lymph nodes, suggesting its involvement in inflammatory reactions to these threats. The precise natural ligands for TREM-1 are not fully identified, but evidence suggests they may include pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), which are released during tissue injury.
TREM-1’s Involvement in Major Diseases
TREM-1’s dysregulation contributes to the pathology of several major diseases by exacerbating inflammatory responses. In sepsis, a life-threatening condition caused by the body’s overwhelming response to infection, TREM-1 is a mediator of the hyperinflammatory state. Elevated expression of TREM-1 on immune cells and increased circulating levels of its soluble form (sTREM-1) are observed in septic patients and are associated with increased mortality. Blocking TREM-1 in animal models of sepsis has demonstrated reduced inflammation and improved survival, highlighting its role in the progression and severity of this condition.
In inflammatory bowel disease (IBD), a chronic inflammatory condition affecting the digestive tract, TREM-1 plays a role in perpetuating intestinal inflammation. While normally expressed on neutrophils and monocytes in a healthy bowel, TREM-1 positive macrophages are detected in the inflamed mucosa of IBD patients. These TREM-1-expressing macrophages exhibit a pro-inflammatory phenotype, contributing to increased production of cytokines such as TNF-α, IL-6, IL-8, and MCP-1 in the gut. Studies in mouse models of colitis have shown that inhibiting TREM-1 can reduce intestinal inflammation and improve disease outcomes.
TREM-1 also contributes to the progression of certain cancers by fostering an inflammatory microenvironment that promotes tumor growth and metastasis. Chronic inflammation is a known driver in the development and progression of various cancers, including colorectal carcinoma. High levels of TREM-1 or its soluble form have been linked to poorer survival in several solid malignancies, such as hepatocellular carcinoma and lung cancer. In colorectal tumors, TREM-1 expression is increased, particularly within tumor-infiltrating neutrophils, and its inhibition has been shown to reduce tumor development in animal models of inflammation-driven tumorigenesis.
Developing Treatments Targeting TREM-1
TREM-1’s involvement in amplifying inflammation across various diseases makes it a promising target for therapeutic intervention. Researchers are exploring strategies to modulate its activity to reduce excessive inflammation without compromising beneficial immune responses. One approach involves developing inhibitors that block TREM-1’s signaling pathways. These inhibitors aim to prevent the interaction between TREM-1 and its ligands or interfere with the intracellular signaling molecules that propagate inflammatory signals.
Different molecules are being investigated as TREM-1 inhibitors, including peptides, small molecules, and monoclonal antibodies. Decoy peptides, such as LP17 and LR12 (nangibotide), bind to TREM-1 ligands, preventing receptor activation. Another strategy involves developing anti-TREM-1 blocking antibodies that directly bind to the TREM-1 receptor to prevent its activation. These approaches aim to temper the overactive immune response seen in inflammatory conditions.
Despite promising preclinical results in animal models for various conditions like sepsis, inflammatory bowel disease, and certain cancers, translating these therapies to human patients has presented challenges. For instance, a clinical trial for the TREM-1 inhibitor nangibotide in sepsis did not meet its primary endpoint, highlighting the complexities of targeting multi-ligand receptors. Researchers are now exploring ligand-independent inhibition strategies, such as peptide GF9, which aims to disrupt the interaction between TREM-1 and its signaling partner DAP12, blocking downstream signaling regardless of ligand binding. The goal of these treatments is to precisely tune the immune response, reducing harmful inflammation while preserving the body’s ability to fight infections and heal.