TREM and TREM-like receptors in inflammation and disease

Abstract

Since the discovery of triggering receptor expressed on myeloid cells (TREM)-1 in 2000, evidence documenting the profound ability of the TREM and TREM-like receptors to regulate inflammation has rapidly accumulated. Monocytes, macrophages, myeloid dendritic cells, plasmacytoid dendritic cells, neutrophils, microglia, osteoclasts, and platelets all express at least one member of the TREM family, underscoring the importance of these proteins in the regulation of innate resistance. Recent work on the TREM family includes: characterization of a new receptor expressed on plasmacytoid dendritic cells; definition of a key role for TREM in inflammatory bowel disease and multiple sclerosis; an expanded list of diseases associated with the release of soluble forms of TREM proteins; and identification of the first well characterized TREM ligand: B7-H3, a ligand for TREM-like Transcript (TLT)-2. Moreover, analysis of TREM signaling has now identified key regulatory components and defined pathways that may be responsible for the complex functional interactions between the TREM and toll-like receptors. In addition, there is expanding evidence of a role for TREM in the regulation of integrin function via Plexin-A1. Together these new findings define the TREM and TREM-like receptors as pluripotent modifiers of disease through the integration of inflammatory signals with those associated with leukocyte adhesion.

Figures

Figure 1

Figure 1. TREM Family of Receptors. Localization of TREM genes on mouse chromosome 17C (left) and human chromosome 6p21.1 (right). Genes shown in green are either known or predicted to associate with DAP12. Those shown in red contain an ITIM motif(s). Treml2, shown in gray, neither associates with DAP12 nor has an ITIM. Where known, TREM expression is indicated. pDC (plasmacytoid dendritic cells), PMN (polymorphonuclear leukocytes), M (monocytes), Mφ(macrophages), BMDC (bone marrow-derived dendritic cells), B (B lymphocytes), DC (dendritic cells), iDC (immature dendritic cells), T (T lymphocytes), Mi (microglia), OC (osteoclasts), Plts (platelets), Meg (megakaryocytes). Ligand identity or lack thereof is listed in parentheses underneath the cell type(s) expressing TREM. Diagram is representative of TREM chromosomal location but is not drawn to scale. C and T define the centromeric and telomeric ends of the chromosome, respectively. See text for references regarding the expression profiles of the TREM.

Figure 2

TLT-1 Signaling Intermediates. The cytoplasmic domain of TLT-1 has an ITIM (red box) that when phosphorylated binds both SHP-1 and SHP-2 protein phosphatases. In transfectants, binding of SHP-2 by TLT-1 potentiates Fc receptor (FcR) signaling through an unknown mechanism. The carboxyl-terminus of TLT-1 also binds the FERM domains of Ezrin, Radixin, and Moesin in platelets. These ERMs couple integral membrane proteins to the actin cytoskeleton, providing a mechanism for TLT-1-mediated enhancement of platelet aggregation.

Figure 3

Potential Networks of TREM Crosstalk with Multiple Immune Signaling Pathways. Engagement of DAP12-coupled TREM leads to phosphorylation of DAP12 on its cytoplasmic ITAM (Green boxes) and recruitment of the kinase Syk. Both TREM-1 and -2 also lead to Syk-mediated phosphorylation of the adaptor NTAL/LAB. NTAL/LAB negatively regulates TREM signals, including Syk activation and calcium mobilization, although its effects on Erk are controversial. Although the mechanism of interaction between TREM and TLR signaling remains unknown, both receptor systems activate Erk and can utilize the Malt1/Bcl10/CARD9 complex to stimulate NF-κB, suggesting regulation of this complex may be critical in understanding how TREMs can either accentuate or repress TLR responses, depending on cellular context. Integrin engagement leads to DAP12 phosphorylation, resulting in calcium mobilization and activation of calcium activated protein kinase (CaMK). Although it is not known whether TREM-associated DAP12 is the target of integrin signaling, CaMK, via the tyrosine kinase Pyk2, enhances the expression of STAT-1 and potentiates the activation of STAT-1 downstream of type I interferon receptors, providing a potential mechanism for TREM modification of cytokine signaling. TREM-2 and PDC-TREM also physically interact with Plexin-A1, suggesting they form a feedback loop for the regulation of integrins. Phosphorylation of Plexin-A1, possibly via Fes, Fyn, or DAP12-associated Syk, modifies the RasGAP activity of its cytoplasmic tail, leading to suppression of R-Ras and reductions in integrin affinity. Therefore, DAP12-coupled TREM have the potential to modify TLR, cytokine, integrin, and ITAM signaling, but more work is needed to fully understand these interactions.