Emerging roles for triggering receptor expressed on myeloid cells receptor family signaling in inflammatory diseases

Abstract

Innate immune receptors represent important therapeutic targets for inflammatory disorders. In particular, the Toll-like receptor (TLR) family has emerged as a promoter of chronic inflammation that contributes to obesity, insulin resistance and atherosclerosis. Importantly, triggering receptor expressed on myeloid cells-1 (TREM-1) has been characterized as an ‘amplifier’ of TLR2 and TLR4 signaling. TREM-1- and TREM-2-dependent signaling, as opposed to TREM-like transcript-1 (TLT-1 or TREML1), are mediated through association with the transmembrane adaptor DNAX activation protein of 12 kDa (DAP12). Recessive inheritance of rare mutations in DAP12 or TREM-2 results in a disorder called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, and surprisingly these subjects are not immunocompromised. Recent progress into the roles of TREM/DAP12 signaling is critically reviewed here with a focus on metabolic, cardiovascular and inflammatory diseases. The expanding repertoire of putative ligands for TREM receptors is also discussed.

Keywords::

• cardiovascular disease
• DNAX activation protein of 12 kDa
• high-mobility group box 1
• inflammation
• metabolic syndrome
• Toll-like receptors
• triggering receptor expressed on myeloid cells

Disclaimer

The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Financial & competing interests disclosure

This work was supported by research grants to DK Agrawal from the NIH, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• TREM receptors play important roles in innate immunity in addition to metabolism, cardiovascular and respiratory systems.

• Mutations in either TREM-2 or DAP12 cause the same disorder characterized by bone cysts and dementia, but these subjects are not immunocompromised.

• Inflammatory diseases including respiratory infections and obesity are associated with increased circulating sTREM-1 levels.

• High-mobility group box 1 is a novel TREM-1 ligand and is also increased in the sera of patients with various vascular diseases.

• TREM-1 inhibition or loss of function can dampen inflammation but can also worsen survival due to impaired pathogen clearance.

• Pharmacological modulation of TREMs represents a novel therapeutic approach to treating inflammatory diseases.

Notes