What Is TREM-1? Its Role in Immunity, Disease, and Therapy

TREM-1, short for triggering receptor expressed on myeloid cells 1, is a protein on the surface of key immune cells that acts as a volume knob for inflammation. When infections or tissue damage trip the immune system’s alarm, TREM-1 amplifies the response, ramping up the production of inflammatory signals far beyond what other receptors achieve alone. Discovered in 2000, it has since been linked to conditions ranging from septic shock to cancer, and blocking it has become a serious target for drug development.

Where TREM-1 Lives and What It Looks Like

TREM-1 sits on the surface of neutrophils and monocytes, two of the immune system’s first responders. Neutrophils are the cells that swarm to sites of bacterial infection within minutes; monocytes patrol the blood and mature into macrophages once they enter tissues. In healthy people, TREM-1 expression on these cells is relatively low. It spikes when the body encounters bacteria or other danger signals.

Structurally, TREM-1 belongs to the immunoglobulin superfamily. Its extracellular portion folds into what scientists call a V-type immunoglobulin domain, a shape shared by parts of antibodies and other immune receptors.¹ Crystal structures show that TREM-1 pairs up into a dimer, and the way the two copies join is unusual: they arrange in a “head-to-tail” orientation, creating two separate spots where activating molecules can dock.² That twin-binding architecture hints at why TREM-1 is such an effective amplifier: it can engage multiple signals at once.

How TREM-1 Fires Up the Immune Response

TREM-1 cannot signal on its own. Its short intracellular tail lacks the machinery to relay messages inside the cell. Instead, it partners with an adaptor protein called DAP12. When something triggers TREM-1, DAP12’s internal signaling segment gets chemically tagged, which recruits enzymes that launch a cascade ending in the activation of pathways that tell the cell to produce inflammatory molecules.³ Without DAP12, TREM-1 is essentially mute.

What makes TREM-1 distinctive is not that it triggers inflammation on its own, but that it massively boosts the inflammatory output already being generated by other receptors. Toll-like receptors (TLRs) are the immune system’s main pattern-recognition sensors; they detect bacterial components and start an inflammatory response. When TREM-1 is activated alongside TLRs, the resulting inflammation is far greater than what either receptor produces individually. Research has shown that the two systems cross-talk at multiple levels, producing synergistic bursts of certain inflammatory proteins.⁴ The activation of TREM-1 itself appears to be driven by both pathogen-derived molecules and damage signals released by injured tissue, along with physical clustering of TREM-1 molecules on the cell surface.⁵

TREM-1 and Sepsis

Sepsis is the disease context where TREM-1’s role was first and most dramatically demonstrated. In a landmark study published in Nature, researchers showed that TREM-1 is expressed at high levels on neutrophils and monocytes infiltrating infected human tissues and is further upregulated in patients with microbial sepsis. Blocking TREM-1 in mouse models protected the animals against septic shock caused by bacterial toxins and live bacteria.⁶ That finding reframed TREM-1 as more than a bystander: it was a critical driver of the runaway inflammation that makes sepsis lethal.

Subsequent work confirmed that once TREM-1 is activated, it triggers the release of inflammatory cytokines and chemokines while also increasing its own expression, creating a self-reinforcing loop. Septic patients show elevated TREM-1 on their immune cells, and those higher levels are associated with worse outcomes.⁷ This positive-feedback behavior is exactly the kind of mechanism that can push a controlled immune response into organ-damaging territory.

Soluble TREM-1 as a Diagnostic Clue

Part of the TREM-1 protein can be cleaved from the cell surface and released into body fluids. This fragment, called soluble TREM-1 (sTREM-1), is detectable in blood, urine, and other fluids, and it rises sharply during infections. Research has found that sTREM-1 levels can help with early diagnosis and outcome prediction across a wide range of infectious diseases, including pneumonia, sepsis, bacterial meningitis, certain viral hemorrhagic fevers, and fungal infections. In some comparisons, sTREM-1 has performed better than older markers like C-reactive protein and procalcitonin for identifying active infection.⁸

A large study of hospitalized patients with infection in a tropical, middle-income setting found that sTREM-1 by itself predicted mortality about as well as a combination of standard clinical variables. When sTREM-1 was added to those clinical variables, the prediction improved further.⁹ That kind of additive value is what clinicians look for in a biomarker: not a replacement for clinical judgment, but a number that sharpens it. The practical appeal is speed. sTREM-1 can be measured from a simple blood draw, and because it tracks the intensity of immune activation in real time, it rises early enough to potentially guide treatment decisions before a patient deteriorates.

Inflammatory Bowel Disease

The gut houses more immune cells than any other organ, and TREM-1 turns out to play a meaningful role in the chronic intestinal inflammation seen in Crohn’s disease and ulcerative colitis. Studies of tissue samples from patients with inflammatory bowel disease (IBD) found a substantial increase in macrophages expressing TREM-1 in the inflamed intestinal lining. In healthy gut tissue, only a few macrophages carry TREM-1 on their surface; in active IBD lesions, roughly 30 to 40 percent of intestinal macrophages expressed it.¹⁰

More recent work has confirmed that TREM-1 gene expression rises in the intestinal lining of IBD patients and that the frequency of TREM-1-positive cells correlates with inflammatory markers. In Crohn’s disease specifically, these cells are mostly immature macrophages and certain granulocytes, and their numbers track with the production of inflammatory molecules in the surrounding tissue.¹¹ The picture that emerges is that TREM-1 helps convert a transient immune response in the gut into sustained, tissue-damaging inflammation. Interestingly, circulating sTREM-1 levels are also elevated in IBD patients, though those blood levels do not always correlate neatly with what is happening at the tissue level.¹² That disconnect is a reminder that a blood biomarker and the local process it reflects are not always moving in lockstep.

Rheumatoid Arthritis

In rheumatoid arthritis (RA), the immune system attacks the tissue lining the joints, and TREM-1 appears to fan those flames. TREM-1 expression in RA joint tissue is markedly higher than in healthy tissue, with one study reporting a more than sixfold increase in TREM-1 messenger RNA in human RA samples. In a mouse model of the disease, the increase was even more dramatic. The TREM-1-positive cells in the joint co-expressed markers for monocytes, and artificially activating TREM-1 in RA joint tissue cultures triggered production of multiple inflammatory proteins.¹³

The mechanism linking the joint environment to TREM-1 has been partly worked out. Fibroblasts in the RA joint, when activated by immune signals, release prostaglandin E2 through a COX-2-dependent pathway, and that prostaglandin drives monocytes to ramp up their TREM-1 expression.¹⁴ Elevated TREM-1 in the joint has been identified as a biomarker for disease activity and is thought to contribute directly to the tissue destruction and chronic joint inflammation that characterize RA.¹⁵ In neutrophils from RA patients, disabling DAP12 blocks TREM-1 signaling entirely, confirming that the same TREM-1/DAP12 partnership operating in sepsis is active in the arthritic joint.³

Atherosclerosis and Heart Disease

Atherosclerosis, the buildup of fatty plaques in arteries, is now understood as an inflammatory disease at its core, and TREM-1 has been shown to accelerate it. In a genetically engineered mouse model prone to atherosclerosis, eliminating TREM-1 from bone marrow-derived cells led to a strong reduction in plaque size in both the aortic root and the larger aorta. Plaques that did form were less inflamed. The study found that TREM-1 promoted the recruitment of monocytes into plaques and boosted the TLR4-driven inflammatory responses of macrophages within them. It also played a critical role in upregulating CD36, a receptor that causes macrophages to gorge on oxidized fats and become inflammatory foam cells, the hallmark cell type in dangerous plaques.¹⁶ These findings suggest that TREM-1 is not just relevant in acute infections; it is a player in the slow-burn inflammation underlying cardiovascular disease.

TREM-1 in Cancer

Tumors are surrounded by immune cells, and many of those cells express TREM-1. In non-small cell lung cancer, the TREM-1-positive cells within the tumor were identified specifically as tumor-associated macrophages (TAMs), not the cancer cells themselves.¹⁷ This distinction matters. The cancer is not making TREM-1; instead, the tumor environment is reprogramming nearby immune cells to express it, and those TREM-1-positive macrophages then help the tumor survive.

The liver cancer story is especially detailed. In mouse models, deleting TREM-1 dramatically reduced the development of liver tumors induced by a chemical carcinogen. While all normal mice developed multiple large tumors by 14 months, only about 4 percent of TREM-1-deficient mice developed any tumors at all, and those were small.¹⁸ TREM-1 was found to be a key regulator of Kupffer cell activation in the liver, driving the chronic inflammatory responses and fibrosis that precede cancer in that organ.¹⁹ TREM-1 expression was also found on activated hepatic stellate cells, where it was associated with more aggressive tumor behavior.²⁰

In advanced liver cancer, the situation gets more complicated. TREM-1-positive TAMs accumulate as tumors progress and create an immunosuppressive environment. They impair the ability of killer T cells to attack the tumor and induce those T cells to die. They also recruit regulatory T cells that further dampen anti-tumor immunity. Critically, TREM-1-positive TAMs were found to undermine the effectiveness of anti-PD-L1 immunotherapy, one of the most widely used modern cancer treatments, through a pathway independent of PD-L1 itself. Blocking the TREM-1 pathway in these models slowed tumor growth and restored the effectiveness of anti-PD-L1 therapy.²¹ That last finding has generated considerable excitement because resistance to checkpoint immunotherapy is one of the biggest unsolved problems in oncology.

Brain Injury and Stroke

TREM-1 is not normally thought of as a brain receptor, but microglia, the brain’s resident immune cells, can express it after injury. In experimental stroke models, TREM-1 expression on microglia surged after blood flow to the brain was cut off. Blocking TREM-1 with a synthetic peptide called LP17 reduced the size of the resulting brain damage and decreased neuronal injury. The peptide dampened the inflammatory activation of microglia, reduced the recruitment of neutrophils into the damaged brain tissue, and lowered markers of oxidative stress.²²

Further investigation revealed that TREM-1 in the brain after stroke contributes to a form of inflammatory cell death called pyroptosis, in which microglia essentially burst open and spill their inflammatory contents into the surrounding tissue. Inhibiting TREM-1 reduced the levels of key pyroptosis-related proteins and curbed the release of inflammatory cytokines while increasing anti-inflammatory ones.²³ These are still animal studies, and the leap from protecting mice from stroke to treating human patients is large. But the consistency of the findings across multiple research groups has put TREM-1 on the radar as a potential neuroinflammation target.

COVID-19 and Viral Lung Injury

TREM-1 is upregulated in acute respiratory distress syndrome (ARDS), including the severe lung inflammation seen in COVID-19. A systematic review and meta-analysis of clinical studies found evidence supporting a pro-inflammatory role for TREM-1 in viral pneumonias, where it contributes to the inflammatory cascade and disease progression.²⁴ The logic is the same as in sepsis: the virus triggers an immune response, and TREM-1 amplifies that response past the point where it helps, contributing to the lung damage that makes severe COVID-19 and other viral pneumonias fatal.

TREM-1 Versus TREM-2

TREM-1 has a close relative called TREM-2, and their relationship is something like a gas pedal and a brake. Since both were discovered in 2000, research has broadly characterized TREM-1 as an amplifier of immune responses and TREM-2 as a negative regulator that damps inflammation down.²⁵ TREM-2 has received enormous attention in neuroscience because mutations in the gene encoding it are among the strongest genetic risk factors for Alzheimer’s disease. The two receptors use the same signaling partner, DAP12, but push the immune system in opposite directions. Understanding how cells balance TREM-1 and TREM-2 signaling is an active and tangled area of research, because flipping either one too far in either direction causes problems.

Therapeutic Approaches Targeting TREM-1

The clearest path toward TREM-1 therapy runs through sepsis. Nangibotide is a synthetic peptide designed to inhibit TREM-1 and was the first TREM-1-targeted agent to enter human trials. A first-in-human safety study established that it was well tolerated in healthy volunteers.²⁶ It then advanced to a Phase 2a trial in patients with septic shock, where animal models had already shown it could restore blood vessel function and improve survival.²⁷ As of the latest published data, nangibotide remains the most advanced TREM-1-targeting therapy, though the gap between promising Phase 2 results and a proven treatment is substantial.

Beyond peptides, researchers are exploring small-molecule inhibitors that could be taken orally rather than infused. A recent screening effort developed cell-based assays to test compounds that disrupt the physical assembly of the TREM-1/DAP12 complex. The pilot screen identified several chemical scaffolds capable of blocking DAP12 dimerization, TREM-1 dimerization, or the interaction between the two proteins.²⁸ These are early-stage laboratory results, not drugs. But they represent a different strategic approach: rather than blocking the receptor after it has been activated, they aim to prevent the receptor complex from assembling in the first place. If any of these scaffolds can be refined into drug candidates, they could eventually offer treatments for chronic inflammatory conditions where a daily pill is far more practical than an infusion.

The cancer angle adds yet another dimension. Because TREM-1-positive macrophages can undermine checkpoint immunotherapy in liver cancer, combining a TREM-1 inhibitor with existing anti-PD-L1 drugs could, in theory, overcome resistance in patients who do not respond to immunotherapy alone.²¹ No combination trials in humans have been reported yet, but the preclinical rationale has attracted attention from both academic groups and pharmaceutical companies looking for ways to expand the reach of immunotherapy.

Why the Ligand Question Still Matters

For a receptor discovered a quarter century ago, one of the most surprising gaps in the TREM-1 story is that its primary natural ligand, the specific molecule in the body that activates it under normal conditions, has not been definitively pinned down. Researchers know that both pathogen-derived and damage-associated molecules can trigger TREM-1, and that physical clustering of the receptor on the cell surface contributes to activation.⁵ But unlike many immune receptors whose activating partners were identified shortly after the receptor itself, TREM-1’s ligand identity remains a contested topic. This is not just an academic puzzle. The design of effective drugs depends on knowing exactly what you are blocking. If TREM-1 has multiple ligands, a drug that blocks one may leave others free to activate the receptor. If it is primarily activated by clustering rather than a single ligand, then therapies aimed at disrupting the receptor’s physical assembly, like the small-molecule approach described above, may prove more effective than ligand-blocking strategies. The answer to the ligand question could ultimately determine which class of TREM-1 therapy wins out.