Chronic inflammation and cancer: emerging roles of triggering receptors expressed on myeloid cells

Abstract

Inflammation is tightly regulated by a vast system that is intricately interconnected with innate immunity. Aberrations in expression or signaling, such as in innate immune receptors, can create excessive inflammation and, when chronic, often promote oncogenesis. The triggering receptor expressed on myeloid cells receptor family has been characterized as a major player in the amplification and signaling of the inflammatory response. In a number of chronic inflammatory conditions and malignancies, the triggering receptor expressed on myeloid cells has been implicated in disease severity and progression. In this article, the current understanding of triggering receptor expressed on myeloid cells function in pre-malignant, malignant and chronic inflammatory conditions is critically reviewed. The potential for therapeutic application is also discussed.

Keywords:

• chronic inflammation
• colorectal cancer
• hepatocellular carcinoma
• inflammatory bowel disease
• leukemia
• neoplastic disease
• non small cell lung cancer
• TREM-1
• TREM-2
• triggering receptor expressed on myeloid cells

Financial & competing interest’s disclosure

This work was supported by research grants R01 HL106042, R01 HL112597, and R01 HL120659 to DK Agrawal from the Office of the Director of National Institutes of Health and the National Heart Lung and Blood Institute, NIH, USA. 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, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest 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

• Triggering receptors expressed on myeloid cells (TREM) play important roles in the inflammatory response and innate immune signaling.

• High-mobility group box 1 has been shown to bind TREM-1 along with other inflammatory receptors, including Toll-like receptors and receptor for advanced glycation endproducts. The peptidoglycan recognition protein 1, when complexed with bacterially derived peptidoglycan, has also been identified as a ligand for TREM-1. However, other TREM ligands have yet to be characterized.

• Growing evidence implicates TREM involvement in chronic inflammatory diseases, rather than solely pathogen-induced acute inflammation.

• Solid tumors are associated with upregulation of TREM-1 on infiltrating myelocytes, whereas leukemia cells unexpectedly demonstrate lower surface TREM-1 levels.

• Functions in addition to the traditional pro-/anti-inflammatory paradigm may exist for TREM-1 and -2, including immune cell migration and non-immune cell proliferation, respectively.

• Evidence in animal models suggests modulation of TREM activity could attenuate excessive inflammatory disorders. This represents significant therapeutic potential for TREM as a pharmacological target.

Notes