TREM-2 promotes acquired cholesteatoma-induced bone destruction by modulating TLR4 signaling pathway and osteoclasts activation

Abstract

Triggering receptor expressed on myeloid cells (TREM) has been broadly studied in inflammatory disease. However, the expression and function of TREM-2 remain undiscovered in acquired cholesteatoma. The expression of TREM-2 was significantly higher in human acquired cholesteatoma than in normal skin from the external auditory canal, and its expression level was positively correlated with the severity of bone destruction. Furthermore, TREM-2 was mainly expressed on dendritic cells (DCs). In human acquired cholesteatoma, the expression of proinflammatory cytokines (IL-1β, TNF-α and IL-6) and matrix metalloproteinases (MMP-2, MMP-8 and MMP-9) were up-regulated, and their expression levels were positively correlated with TREM-2 expression. Osteoclasts were activated in human acquired cholesteatoma. In an animal model, TREM-2 was up-regulated in mice with experimentally acquired cholesteatoma. TREM-2 deficiency impaired the maturation of experimentally acquired cholesteatoma and protected against bone destruction induced by experimentally acquired cholesteatoma. Additional data showed that TREM-2 up-regulated IL-1β and IL-6 expression via TLR4 instead of the TLR2 signaling pathway and promoted MMP-2 and MMP-8 secretion and osteoclast activation in experimentally acquired cholesteatoma. Therefore, TREM-2 might enhance acquired cholesteatoma-induced bone destruction by amplifying the inflammatory response via TLR4 signaling pathways and promoting MMP secretion and osteoclast activation.

Increased TREM-2 expression on the subsets of CD11c+ cells in the lungs and lymph nodes during allergic airway inflammation

“…When expressed on macrophages and microglia, TREM-2 seems to play more of an anti-inflammatory role 29 , 42 , 43 . However, based on the results from our studies as well as other groups, when expressed on dendritic cells, the role seems to be reversed 25 , 30 . It is our speculation that the receptor could be contributing to allergic airway inflammation by amplifying pro-inflammatory signals generated by TLRs or other DAP-12 DC associated receptors ultimately resulting in increased survival, maturation and migration of DC subsets.…”

“…Although the receptor has been implicated in a number of disease models 17 , 21 , 31 , 32 , its expression and function has not been clearly elucidated in allergic airway inflammation. As seen with other inflammatory conditions 20 , 22 , 25 , 30 , 31 , TREM-2 was found to be upregulated in the airways of mice exposed to OVA when compared to the control groups. In steady state, TREM-2 was expressed on all subsets of DCs identified in the lungs confirming that DCs do express TREM-2.…”

“…It is generally regarded as an anti-inflammatory mediator but has been shown to amplify the production of pro-inflammatory cytokines and upregulate CCR7 expression, which is crucial for migration of dendritic cells to the draining lymph nodes 18 , 24 , 25 , 29 . Recently, TREM-2 has also been shown to be upregulated on DCs that contribute to bone destruction in a murine model of acquired cholesteatoma 30 .…”

The extra domain A of fibronectin facilitates osteoclastogenesis in radicular cysts through vascular endothelial growth factor

“…Fibroblasts of odontogenic cysts have been demonstrated as favourable for osteoclast formation in previous studies (Wang & Li , Wang et al 2015a, Wang et al 2015b). This may be partly attributed to the interaction between the EDA fragment and pre‐osteoclasts or fibroblasts, hence contributing to osteoclastogenesis either directly or indirectly (Gondokaryono et al , Shinde et al , Xiang et al , Doddapattar et al , Jiang et al ).…”

“…The effects of FN isoforms on osteoclastogenesis may contribute to bone destruction due to the inflammatory microenvironment of radicular cysts (Khan et al , Khan et al , Liu et al ). Since the three main splice variants, EDA + FN, EDB + FN and CS1‐FN, are ligands of integrin receptors and Toll‐like receptor 4 (TLR4), interactions between FN isoforms and receptors in pre‐osteoclasts may directly affect osteoclastogenesis (Doddapattar et al , Jiang et al ), whilst their interaction in other cells could alter the expression of osteoclastogenic genes, such as vascular endothelial growth factor (VEGF) or IL‐17 (Liu et al , Lv et al ), by which osteoclastogenesis can be indirectly influenced. Therefore, this study explored the effects of FN isoforms on bone destruction in radicular cysts, as well as the underlying mechanism through antibody blocking and gene editing using the type II bacterial clustered, regularly interspaced, palindromic repeats (CRISPR)‐associated (Cas) system (Kohan et al , Wang et al 2015a, Wang et al 2015b).…”