TREM-1 Is Upregulated in Experimental Periodontitis, and Its Blockade Inhibits IL-17A and RANKL Expression and Suppresses Bone loss.

George Hajishengallis,Nagihan Bostanci,Georgios N Belibasakis,Toshiharu Abe

doi:10.3390/jcm8101579

Abstract

Aim: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a modifier of local and systemic inflammation. There is clinical evidence implicating TREM-1 in the pathogenesis of periodontitis. However, a cause-and-effect relationship has yet to be demonstrated, as is the underlying mechanism. The aim of this study was to elucidate the role of TREM-1 using the murine ligature-induced periodontitis model. Methods: A synthetic antagonistic LP17 peptide or sham control was microinjected locally into the palatal gingiva of the ligated molar teeth. Results: Mice treated with the LP17 inhibitor developed significantly less bone loss as compared to sham-treated mice, although there were no differences in total bacterial load on the ligatures. To elucidate the impact of LP17 on the host response, we analyzed the expression of a number of immune-modulating genes. The LP17 peptide altered the expression of 27/92 genes ≥ two-fold, but only interleukin (IL)-17A was significantly downregulated (4.9-fold). Importantly, LP17 also significantly downregulated the receptor activator of nuclear factor kappa-B-ligand (RANKL) to osteoprotegerin (OPG) ratio that drives osteoclastic bone resorption in periodontitis. Conclusion: Our findings show for the first time that TREM-1 regulates the IL-17A-RANKL/OPG axis and bone loss in experimental periodontitis, and its therapeutic blockade may pave the way to a novel treatment for human periodontitis.

Highlights

Periodontitis entails the destruction of the tooth-supporting tissues, as an outcome of their inflammatory response to the juxtaposed microbial biofilm forming on the tooth surface [1,2]
The inflammatory mediators that lead to alveolar bone destruction form an intricate network [3,4], in which the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) system plays a crucial role as a terminal regulator of the resulting osteoclastogenesis and bone resorption [5,6]
Using the ligature-induced murine periodontitis model, we first investigated the regulation of Triggering receptor expressed on myeloid cells 1 (TREM-1) expression in the gingival tissue

Summary

Introduction

Periodontitis entails the destruction of the tooth-supporting (periodontal) tissues, as an outcome of their inflammatory response to the juxtaposed microbial biofilm forming on the tooth surface [1,2]. The inflammatory mediators that lead to alveolar bone destruction form an intricate network [3,4], in which the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) system plays a crucial role as a terminal regulator of the resulting osteoclastogenesis and bone resorption [5,6]. Bacterial infection can upregulate the membrane-bound and soluble forms of TREM-1, which in turn amplifies inflammation. This is a crucial response associated with systemic sepsis [10,11]. The study by Weber et al [13] suggested that TREM-1 regulates inflammation, and that its therapeutic targeting may be beneficial in infection-driven inflammatory diseases without compromising pathogen clearance

Objectives

Methods

Results