LOX-1 is involved in IL-1β production and extracellular matrix breakdown in dental peri-implantitis

Highlights

• LOX-1, IL-1β, MMP2 and MMP9 are involved in human dental peri-implantitis.

• LOX-1 reduces P. gingivalis induced IL-1β production in macrophages.

• JNK was responsible for LOX-1 induced IL-1β production upon P. gingivalis infection.

• P. gingivalis induced MMP2 and MMP9 production in macrophages is dependent on LOX-1.

Abstract

Purpose

To explore whether lectin-type oxidized LDL receptor 1 (LOX-1), interleukin 1 beta (IL-1β), matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) are involved in the nosogenesis of human dental peri-implantitis and determine the role of LOX-1 in IL-1β, MMP2 and MMP9 production in response to Porphyromonas gingivalis.

Methods

Peri-implant crevicular fluid (PICF) was collected from ten patients with healthy implants and ten patients with peri-implantitis. The LOX-1 protein in PICF was detected by Western-blot, and the expression of LOX-1 in superficial gingiva of peri-implantitis patients was detected by immunofluorescence staining. The IL-1β, MMP2 and MMP9 proteins in PICF were detected by enzyme-linked immunosorbent assay (ELISA). THP-1 macrophages were pretreated with neutralizing antibody (LOX-1) and inhibitors (LOX-1 and c-Jun N-terminal kinase, JNK) to evaluate the role of LOX-1 and JNK in IL-1β production, as well as the role of LOX-1 in MMP2 and MMP9 production in response to P. gingivalis by quantitative polymerase chain reaction (RT-PCR) and Western-blot.

Results

LOX-1, IL-1β, MMP2 and MMP9 increased in PICF of peri-implantitis patients and in THP-1 macrophages on P. gingivalis stimulation. IL-1β, MMP2 and MMP9 production in response to P. gingivalis in THP-1 macrophages was dependent on LOX-1. JNK was responsible for LOX-1 induced IL-1β production as a result of P. gingivalis infection.

Conclusion

LOX-1 is involved in IL-1β production and extracellular matrix breakdown is a novel inflammatory pathway trigger and potential drug target in human dental peri-implantitis.

Introduction

A dental implant is one of the most frequently used treatments for tooth replacement in patients [1]. Dental peri-implantitis, an oral inflammatory disease leading to supporting tissues loss, affects approximately 30% of patients [1], [2], [3], [4]. There are various treatment options for peri-implantitis [5], [6], [7], however, there does not appear to be one superior treatment approach proved to be highly effective against peri-implantitis thus far.

Tissues surrounding dental implants and teeth develop an inflammatory reaction in response to microbial infection, including P. gingivalis [8], [9], [10], Prevotella intermedia [11], [12], and Aggregatibacter actinomycetemcomitans [13], [14] infection. The human immune system responds to the bacterial infection by the recruitment of neutrophils, macrophages, T cells, and B cells into the lesion [15], [16], [17], [18]. Compared with periodontitis, peri-implantitis exhibits a more extensive inflammatory infiltrate of innate immunity, severe tissue destruction and faster progression [19], [20]. There have been multiple studies regarding the immunological pathogenesis of periodontal diseases, although the effects of innate immune responses to peri-implantitis have not been thoroughly evaluated [21].

Pattern recognition receptors (PRRs) play a vital role in innate immunity. Pathogen-associated molecular patterns (PAMPs) from microbial pathogens and damage-associated molecular patterns (DAMPs) from released cell components during cell damage or death have been identified by PRRs in innate immunity [22], [23]. Lectin-type oxidized LDL receptor 1 (LOX-1) (also known as oxidized low-density lipoprotein receptor 1, oxLDL receptor 1) is a pattern recognition receptor of the C-type lectin superfamily. In addition to being an oxLDL receptor, LOX-1 is a multi-ligand receptor which binds to activated platelets, apoptotic cells, C-reactive protein, and bacteria [24], [25], [26]. LOX-1 is also involved in P. gingivalis-induced atherosclerosis [27], [28], [29]. However, no previous studies have explored the role of LOX-1 in peri-implantitis.

The present report demonstrated that LOX-1, interleukin 1 beta (IL-1β), matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) were increased in peri-implantitis patients and in human THP-1 macrophages stimulated with P. gingivalis. The LOX-1 induced IL-1β production upon P. gingivalis infection was JNK dependent. Furthermore, LOX-1 also regulated MMP2 and MMP9 production induced by P. gingivalis. These results show that LOX-1 is essential for IL-1β production and extracellular matrix breakdown in peri-implantitis.