Role of triggering receptor expressed on myeloid cells-1 in kidney diseases: A biomarker and potential therapeutic target

Abstract

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.

Trial registration: ClinicalTrials.gov NCT04682431.

Figure 1

The structural diagrams of TREM-1 (by Figdraw). TREM-1 located on human chromosome 6p21 or mouse chromosome 17C. Depending on the transcription, alternative splicing of the TREM-1 encoding gene into sTREM-1 (Ig-like domain) (left). The typical translation process of TREM-1 encoding gene produces mTREM-1, cleavage of MMPs results in sTREM-1 protein production (right). MMPs: Matrix metalloproteinases; TM: Transmembrane; TREM-1: Triggering receptor expressed on myeloid cells-1.

Figure 2

Schematic representation of the TREM-1 signaling pathway (by Figdraw). TREM-1 has two isoforms, membrane-bound (mTREM-1) and soluble (sTREM-1). MMPs cleave mTREM-1 into sTREM-1, which acts as an antagonist of membrane receptors. Upon binding to its ligand, TREM-1 triggers an intracellular signal mediated by DAP12. The ITAM motif in DAP12 is phosphorylated by SRC family kinases, and activated ITAM binds to recruited ZAP 70 and SYK, leading to the activation of PLCγ, PI3K, JAK, and ERK pathways. These pathways regulate Ca²⁺ influx, cell survival, and transcription of several genes involved in the inflammatory response. The tyrosine kinase SYK/ZAP 70 can also activate the NLR pathway, which will merge with the TLR pathway initiated by Myd88. TREM-1 cooperates with the TLR and NLR pathways to amplify inflammation. AP-1: Activator protein 1; DAP12: 12 kDa adap­tor protein molecule DNAX; ERK: Extracellular signal-regulated kinases; GRB2: Growth factor receptor binding protein-2; ITAM: Immune receptor tyrosine-based activation motif; IL: Interleukin; JAK: Janus kinase; LPS: Lipopolysaccharide; MMPs: Matrix metalloproteinases; NF-κB: Nuclear factor κB; NLR: NOD-like receptors; PI3K: Phosphatidylinositol 3-kinase; PLCγ: Phospholipase C gamma; SOS: Son of sevenless protein; SRC: Rous sarcoma oncogene; SYK: Spleen tyrosine kinase; TLRs: Toll-like receptors; TM: Transmembrane; TREM-1: Triggering receptor expressed on myeloid cells-1.

Figure 3

The schema of the role of TREM-1 in kidney diseases (by Figdraw). Under the stimulation of ligands, the activation of TREM-1 signal on different renal cells can promote or amplify the release of inflammatory factors. At the same time, in kidney diseases, the increase of sTREM-1 in serum and urine may be a biomarker of these kidney diseases and may predict poor clinical prognosis in these kidney diseases. At present, some TREM-1 inhibitors such as LR12 (phase 2b clinical trial), LP17, TREM-1-Fc segment, M3 inhibitory peptide, and VD can inhibit the activation of TREM-1. Tozasertib and TPCA-1 combined with immunotherapy, PY159, anti-TREM-1 antibody combined with pembrolizumab may have a certain therapeutic effect on RCC with abnormal TREM-1 expression. The blue short line indicates suppression; brown arrows indicate facilitation or influence. Ab: Antibody; AKI: Acute kidney injury; IgAN: Immunoglobulin A nephropathy; DC: Dendritic cell; DN: Diabetic nephropathy; IgAN: Immunoglobulin A nephropathy; IRI: Ischemia-reperfusion injury; RCC: Renal cell carcinoma; SLE: Systemic lupus erythematosus; TREM-1: Triggering receptor expressed on myeloid cells-1; VD: Vitamin D.