TREM-1 DOES NOT DIRECTLY RECOGNIZE PATHOGENS BUT WORKS SYNERGISTICALLY WITH RECEPTORS TO AMPLIFY THE INFLAMMATORY RESPONSE

Sessa R, Maccauro G. TREM-1 does not directly recognize pathogens but works synergistically with receptors to amplify the inflammatory response. International Journal of Infection. 2026;10(1):16-20.

R. Sessa^1* and G. Maccauro²

¹ Department of Public Health and Infectious Diseases, “Sapienza” University, Rome, Italy;
² Department of Orthopedics, Ageing and Rheumatological Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

*Correspondence to:
Rosa Sessa,
Department of Public Health and Infectious Diseases,
“Sapienza” University,
00185 Rome, Italy.
e-mail: rosasessa@uniroma1.it

Received: 05 January, 2026 Accepted: 23 April, 2026

ISSN 3103-6678 [online] Copyright 2026 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

The triggering receptor expressed on myeloid-1 (TREM-1) is expressed primarily on innate immune cells, such as neutrophils, monocytes/macrophages, and natural killer (NK) cells. Activated TREM-1 amplifies inflammatory signals and enhances the production of TNF, IL-1β, and IL-6. TREM-1 acts indirectly using an adaptor protein, tyrosine kinase-binding protein (TYROBP), which contains the immunoreceptor tyrosine-based activation motif (ITAM)  domain that activates a cascade of intracellular signals. TYROBP does not directly recognize pathogens but transmits signals to immune cells through pathogen recognition receptors (PRRs). TREM-1, expressed on the membranes of immune cells, can cause damage to internal organs when overactivated. The soluble form (sTREM-1), detectable in biological fluids, is a useful marker for infection and inflammation and may represent a potential therapeutic target. TREM-1 amplifies the action of Toll-like receptor complex 4 (TLR4), which is responsible for recognizing microorganisms. Activated TREM-1 triggers an intracellular cascade that includes the recruitment of kinases such as Syk and various activation pathways, such as the mitogen activated protein kinase (MAPK) family of kinases. MAPK induces the production of cytokines such as TNF, IL-1β, and IL-6, and ERK1/2, which cause cell proliferation and survival. In sepsis, activated TREM-1 amplifies the inflammatory response via MAPK. TREM-1 significantly intensifies a rapid and effective immune response, but if left unchecked, it can lead to excessive inflammation and tissue damage, as occurs in sepsis.

KEYWORDS: TREM-1, triggering receptor, inflammation, immune cell, tyrosine kinase binding protein, ITAM, TLR

INTRODUCTION

Triggering receptor expressed on myeloid-1 (TREM-1) is a key immune system receptor that increases inflammatory reactions by amplifying the Toll-like receptor (TLR) response (1). TREM-1 is expressed primarily by phagocytic cells such as neutrophils and monocytes/macrophages of the innate immune system (2).  Activated TREM-1 stimulates intracellular signals, leading to neutrophil degranulation, activation of phagocytosis, and increases cytokine production (3). TREM-1’s function is to amplify inflammatory signals and enhance the production of TNF, IL-1β, and IL-6, as well as playing a key role in the recruitment of immune cells (4).

The biological effect of TREM-1 is not direct but relies on the adaptor protein activation protein of 12 kDa (DAP12), also known as tyrosine kinase binding protein (TYROBP), which contains an immunoreceptor tyrosine-based activation motif (ITAM) domain (5). TYROBP is an adaptor protein that does not directly recognize pathogens but transmits signals within immune cells (6).  Innate immune cells, such as macrophages, microglia, dendritic cells, and natural killer (NK) cells, are those that express TYROBP the most (7). When this protein recognizes a pathogen, it binds to specific receptors on the cell membrane and transmits the signal within the cell (8).

DISCUSSION

The presence of ITAM activates a cascade of intracellular signals (9). ITAM is a set of amino acids present in the internal cytoplasmic portion of some proteins involved in TYROBP immune signalling (10,11). When the cell receptor is activated, the tyrosines in ITAM are phosphorylated, resulting in the activation of a cascade of intracellular signals. These reactions lead to activation of the immune system, resulting in the elimination of the infected cell and the production of cytokines. ITAMs are present in the TYROBP adaptor proteins, in the T-cell receptor (TCR) complex, and in B-cell receptors (BCR) (11). ITAM is important because it activates immune responses against infections and tumor cells, regulates microglia activity, and is involved in various diseases, including immune-related diseases.

In the immune response to infections, TREM-1 does not signal directly on its own, but associates with an adaptor protein and mediates the inflammatory response (12). Its involvement extends to several diseases, including sepsis, where it amplifies the systemic response to infection and inflammation. Over-activation of TREM-1 can result in damage to organs and the entire body (13).

TREM-1 can be expressed on the membranes of immune cells, but soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) can also be detected in the circulation, in biological fluids, such as blood, alveolar, and pleural fluids (14). sTREM-1 is being studied as a useful biomarker for infection and inflammation and as a potential therapeutic target (15).

TREM-1 does not directly recognize pathogens, but amplifies the action of TLRs, which are responsible for recognizing pathogenic microorganisms (16) (Table I). TLRs recognize both pathogens and pathogen components, such as the LPS of Gram-negative bacteria. There is evidence demonstrating that TREM-1 interacts with, or is a component of, the Toll-like receptor complex 4 (TLR4) (17). The action of TLRs activates an initial immune response, in which TREM-1 is upregulated and amplifies the signal (18). These effects lead to excessive production of cytokines and chemokines that mediate immunity and the inflammatory response (19). TREM-1 interacts with TLRs to recognize microorganisms, causing a synergistic response (20).

Table I. Activation of triggering receptor expressed on myeloid-1 (TREM-1)leads to an intracellular cascade that culminates in the production of pro-inflammatory cytokines.

In sepsis, an uncontrolled systemic inflammatory response to infection, TREM-1 may participate in the induction of the “cytokine storm” that can lead to septic shock (21). Bacteria or their microbial products, such as pathogen-associated molecular patterns (PAMPs) (LPS or peptidoglycans), are recognized by TLRs and activate the immune response (22). TREM-1 activation leads to an amplification of cytokine production induced by the second major class of pattern recognition receptors (PRRs), which recognize intracellular microorganisms. NOD-like receptors (NLRs) are one of the second major classes of PRRs, synergizing with TREM-1 to increase the production of TNF, IL-1β, and IL-6 (23).  NLRs do not directly increase TREM-1 but do so indirectly by activating inflammatory pathways that lead to increased TREM-1 expression on immune cells (24). TREM-1 amplifies inflammation induced by stimulation of PRRs. This leads to the production of immune mediators such as cytokines and chemokines. These immune reactions and the TLRs cause the amplification of TREM-1 and the inflammatory response (25). Thus, the immune response is initiated by TLRs binding to the microorganism, and TREM-1 amplifies the inflammatory response (Table II).

Table II. Triggering receptor expressed on myeloid-1 (TREM-1) amplifies Toll-like receptor (TLR) activation and triggers a series of intracellular reactions that lead to increased inflammation.

TREM-1 acts on both TLRs, which are major extracellular bacterial recognition pathways, and intracellular molecules (26). Microbial-activated TREM-1 is expressed by the innate immune system and does not signal alone but through the adaptor TYROBP, which contains immunoreceptor ITAM. TREM-1 activation leads to an intracellular cascade that includes the recruitment of kinases such as Syk and various activation pathways such as the mitogen activated protein kinase (MAPK) family of kinases (ERK, JNK, p38). MAPKs regulate the response to external stimuli, determining specific cellular responses (27). p38 induces the production of cytokines TNF, IL-1β, and IL-6, and that ERK1/2 causes cell proliferation and survival, while Jun N-terminal kinase (JNK) induces the stress response and inflammation (28).  When TREM-1 is activated by microorganisms, it amplifies the inflammatory response via MAPK and NF-κB, leading to the recruitment of immune cells, increased production of cytokines and chemokines, and an amplifying effect on inflammation (29).

The modulation of TREM-1 or MAPK could serve as a therapeutic target for reducing inflammation (30). Inhibition of inflammation can occur with sTREM-1, modulating both the immune and inflammatory responses (12).  Anti-TREM-1 antibodies specifically inhibit LPS-induced TNF production, while blocking TLR4 with a specific inhibitor reduces the effects of TREM-1 cross-linking (31). The TREM-1 inhibitor peptide lipoprotein-like peptide17 (LP17) may have therapeutic implications in reducing inflammation and maintaining an effective immune response (32).  LP17 is a synthetic peptide composed of 17 amino acids that is derived from the extracellular sequence of TREM-1. LP17 acts as a TREM-1 inhibitor and mimics part of the TREM-1 receptor but does not activate the signalling pathway (33). LP17 competes with TREM-1 for ligand binding, blocks activation of the TREM-1-TYROBP complex, and reduces the intracellular NF-κB cascade with systemic inhibition of pro-inflammatory cytokines (34).  LP17 and sTREM-1 both limit the excessive inflammatory response and improve survival in experimental models. The biological effects of TREM-1 may be explained by its interaction with TLR4 activated by the microorganism (20).

CONCLUSIONS

In conclusion, TREM-1 is an important regulator of the innate immune response, even though it does not directly recognize pathogens. TREM-1 acts as a powerful amplifier of inflammatory signals generated by other receptors, such as TLRs. In addition, TREM-1 enhances the immune response and is crucial in diseases characterized by excessive or uncontrolled inflammation. A thorough understanding of the role of TREM-1 opens new perspectives, both for biological research and for the development of new therapeutic strategies against inflammation.

Conflict of interest

The authors declare that they have no conflict of interest.

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