Zhu-Ling Guo, Wan-Yun Lin, Chen Xie, Qi-Ya Fu?

1.Department of Stomatology, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, PR China

2.School of Stomatology, Hainan Medical University, Haikou 570100, PR China

Keywords:

ABSTRACT

Periodontitis is an inflammatory and destructive disease caused by dental plaque bio film, involving periodontal supporting tissue, which makes periodontal tissue lose the ability of regeneration and repair, resulting in tooth loosening and falling off. Periodontitis is a non-communicable disease with high prevalence. About 50% of the world's population is affected by periodontitis, among which 11.2% are severe periodontitis, which is the first cause of tooth loss in adults. As early as the 1970s, some scholars have proved that when gram-negative anaerobic bacteria become the dominant bacteria of subgingival plaque, the antigen released into periodontal tissue will affect the immune response of the body. When the host's immune response is insufficient or overactive, it will cause periodontal tissue steady-state destruction, periodontal tissue damage or periodontitis inclines from static phase to active phase[1-3]. The main virulence molecule of Gram-negative bacteria is endotoxin. Lipopolysaccharide (LPS), as the main active component of endotoxin, can induce the production of proinflammatory cytokines and activate various types of cells, including macrophages, epithelial cells and endothelial cells. It is a typical immune activator. Lipoproteins were initially defined according to their composition, i.e. lipids and proteins, and then classified into chylomicrons (CM), very low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL).

HDL are mainly synthesized from the liver and small intestine and are plasma lipoproteins with the smallest diameter (7.0-20 nm) and the highest density (1.063-1.21 g/ml). HDL includes free or esterified cholesterol, phospholipids, triglycerides and a variety of proteins, including apolipoproteins such as apo-i, apo-ii, apoC-I, Apo-E, lecithin cholesterol acyltransferase and cholesterol ester transfer protein. HDL can be divided into small disk HDL, middle spherical HDL3 and large high cholesterol spherical HDL2. Apo-i binds free cholesterol and phospholipids to form pre β1-HDL. The precursor HDL is gradually metabolized into mature HDL through preβ1-HDL →→preβ2-hdl → HDL3 → HDL2 under the action of lecithin cholesterol acyltransferase. Some research results show that HDL is mainly involved in the reverse transport of cholesterol in vivo, which can effectively remove and reduce the cholesterol level in blood lipids, thus inhibiting the occurrence and development of atherosclerosis[4,5]. In addition, HDL plays a variety of functions such as immune regulation, anti infection and anti-oxidation. Many studies have shown that HDL can bind and neutralize microorganisms or chemicals of microbial origin, such as LPS from Gram-negative bacteria. High density lipoprotein (HDL) is an important part of circulating blood, which plays an important role in vascular endothelial function and immune regulation. This article aims to review the role of high density lipoprotein in periodontitis and periodontitis with systemic diseases.

1. HDL and LPS

1.1 Mechanism of LPS in periodontitis

LPS plays an important role in the pathological process of periodontitis. After binding to its receptor, LPS can activate the cellular immune and inflammatory response system of periodontal tissue defense cells, break the balance between inflammatory mediators and anti-inflammatory mediators, and cause periodontal tissue damage. The specific process is as follows: LPS released by periodontal pathogens binds to lipopolysaccharide binding protein (LBP) in body fluid and CD14 molecule of monocyte to form LBP-LPS-CD14 complex, which is transferred to Toll like receptor 4 (TLR4) on the surface of target cells. On TLR4-MD2 complex, TLR4 activates TLR4 receptor, and TLR4 causes the ubiquitination of tumor necrosis factor associated factor 6 (TRAF6), thus promoting the activation of nuclear factor kappa B (NF -κ b); at the same time, activated TRAF6 can regulate the activation of serine / threonine protein kinase, and then activate activator protein-1 (activator protein-1,AP-1). Through the activation of NF - κB and AP-1, the expression of NLRP3 was up-regulated, and Caspase-1 was activated, which promoted the maturation of pro-IL-1βand pro-IL-8, and secreted IL-1βand IL-8 [4-6]. IL-1 β can activate osteoclasts and T cells, and play a strong role in inflammation; IL-8 induces polymorphonuclear leukocytes(PMN) to chemotaxis and moves out of the epithelium in periodontal tissue. The superoxide ion and lysosomal enzyme cytokine produced in the process of phagocytizing bacteria will aggravate the inflammation of periodontal tissue. In addition, activated NF -κB will further activate nuclear factor of activated T-cells cytosolic 1 (NFATc1), which is an important factor regulating osteoclast production, and induce the expression of a large number of osteoclast specific target genes, thus leading to the formation of osteoclasts more active, resulting in alveolar bone absorption and periodontitis inclining towards the active phase [6-9].

Figure 1: Mechanism of LPS and HDL in periodontitisnote：①HDL:High density lipoprotein ②LBP: lipopolysaccharide binding protein ③TLR4：Toll like receptor 4 ④TRAF6：tumor necrosis factor associated factor 6 ⑤NF-κB：nuclear factor kappa B

1.2 The conbination of HDL to LPS

Experiments showed that HDL could not increase the release of TNF-a, IL-1βand IL-8 in blood [10,11]; other foreign scholars have proved that apo-i and apo-ii can inhibit the activation of neutrophils, reduce their oxidative stress and the production of IL-8 [12]. Other scholars found that there was no significant difference in the mean values of total cholesterol, LDL and VLDL between the study group and the control group, only HDL had a very significant difference between healthy and chronic periodontitis patients [13]; the experiment proved that HDL can reduce the inflammatory reaction of patients; some scholars observed the changes of HDL components by LPS induced acute phase reaction, and confirmed that HDL has anti LPS function [14,15]. In conclusion, HDL has important immunomodulatory properties, including reducing LPS induced inflammatory response. The results showed that the binding of LPS to lipoproteins was highly specific. Compared with VLDL, LDL and cm, HDL had the highest binding capacity with LPS [16,17]. The binding of HDL and LPS is mediated by LBP and soluble CD14 to form lps-hdl particles, which reduces the binding of LPS to TLR4 receptor, down regulates TLR4 Signal Transduction and NF -κB pathway, and reduces the release of inflammatory factors, thus alleviating periodontal injury caused by inflammation [18,19] (Fig.1). HDL can also bind and neutralize LPS through the action of plasma phospholipid transporter, inhibit the binding of LPS with neutrophils, inhibit the network structure that can cause neutrophil activation, thus neutralizing its toxic effect [20,21], reducing the stimulation of inflammatory substances on periodontal tissue and slowing down the development of periodontitis.

2. HDL and antigen presenting cells

There are four types of cells in periodontal ligament: connective tissue cells, Malassez epithelial residual cells, macrophages and other defense cells, as well as nerve and vascular related cells. Macrophages can be activated by microbial products such as LPS, releasing cytokines to promote the development of periodontitis. For example, the latest research in China shows that the expression of tumor necrosis factor- a (TNF- a) in macrophages is up-regulated after LPS stimulation[22]. Dendritic cells (DCS) are important antigen presenting cells in innate and acquired immune responses. They exist in the gingiva and connective tissue of healthy gingiva, gingivitis and periodontitis. When LPS activates TLR4 signaling pathway, it can promote the maturation of DCS, and then promote the expression of MHC II, CD80, CD86 and CD40 on DCS surface, and stimulate the transformation of Th0 cells to Th2, thus inducing the differentiation of B lymphocytes[23]. Recent studies have found that B lymphocytes may be the main source of IL-1 in periodontitis. Both IL-1 and TNF-a can directly stimulate osteoclast proliferation, induce matrix metalloproteinases (MMPs) and up regulate cyclooxygenase-2 (COX-2) to produce prostaglandin E2 (PGE2). MMPs mainly degrade collagen fibers and elastin. PGE2 induces MMPs and osteoclastic bone resorption. These two cytokines play an important role in periodontal tissue destruction. Macrophages also belong to antigen-presenting cells with costimulatory molecules and lipid rafts that activate the adaptive immune system. Fotakis et al. confirmed that recombinant HDL infusion has anti-inflammatory effect in pathological macrophages [24]. The research results of Sini show that dysfunctional HDL can induce lipid accumulation of macrophages and cause pro-inflammatory reaction[25]; some studies have shown that HDL3 and HDL2 promote cholesterol outflow through ATP binding frame transporter G1 and ATP binding frame transporter A1, respectively, so as to reduce or eliminate cholesterol in macrophage lipid rafts and play an anti-inflammatory role [26]. These results suggest that HDL can affect the activation of T cells through macrophages and regulate cell-mediated immune response. In periodontal diseases, cytokines produced by T-helper are responsible for regulating various functions of acquired immune defense response. It can be seen that HDL can slow down periodontal tissue damage by regulating cellular immune response.

3. HDL and periodontitis with systemic diseases

The existing literature has confirmed that HDL is the "lipid scavenger" and "anti-atherosclerotic factor" in blood vessels. The occurrence of coronary heart disease is related to the decrease of HDL concentration. Similarly, C-reactive protein (CRP) as an inflammatory factor, its increased level has been considered as a risk factor of coronary heart disease, through the detection of CRP, HDL indicators for clinical diagnosis of coronary heart disease has important significance. The relationship between CRP and periodontitis has been clear for a few years. By monitoring the changes of serum CRP levels in patients with moderate and severe chronic periodontitis before and after periodontal scaling, the researchers found that the serum CRP of patients with moderate and severe chronic periodontitis without systemic diseases decreased significantly after 3 months of periodontal treatment [27]; mallaprafada et al. He also gave the same conclusion, the serum CRP of patients with periodontitis increased and increased with the severity of periodontitis[28]. In recent years, many domestic and foreign scholars have suggested that periodontal disease is closely related to coronary heart disease, and the incidence rate of periodontal disease is positively correlated. It has been reported that in addition to plasma LDL leading to lipid deposition of vascular wall, chronic inflammation is also the driving force of atherosclerosis[29]. Periodontitis is a typical chronic inflammatory disease. Many scholars believe that chronic periodontitis is an independent risk factor for coronary heart disease, there is a certain correlation between the two, and can affect each other[30,31]. As for the role of inflammation in atherosclerosis, atherosclerosis promotes the release of inflammatory factors. For example, elevated CRP is significantly correlated with the decrease of HDL[32]; domestic scholars' experiments show that the serum levels of IL-1, IL-6, TNF-a and other inflammatory factors in patients with periodontitis are higher than those in healthy periodontitis, and the levels of IL-1, IL-6 and TNF-a in patients with moderate to severe periodontitis and coronary heart disease are also significantly higher than those with periodontitis or coronary heart disease [33]; in addition, subjects were divided into chronic periodontitis group and coronary heart disease group The levels of LDL and HDL in all groups were detected. It was found that the level of serum LDL in healthy control group was lower than that in other groups, and HDL level was higher than that in other groups. It is suggested that there is interaction between inflammatory factors in the serum of patients with periodontitis. With the increase of oxidative stress, HDL will also be modified by oxidation, and the anti-inflammatory ability will be weakened, leading to the deterioration of HDL's endothelial protection effect [34]. In addition to the direct injury of inflammatory factors to endothelial cells, the mechanism can promote the formation of atherosclerotic plaques under the endothelium. Inflammatory factors can also promote the uptake of LDL by mononuclear macrophages, and the transport of LDL-C from phagocytes by HDL will lead to changes in the concentration of LDL-C and HDL-C, which will further induce the formation of foam cells and accelerate atherosclerosis, which may be the pivot of coronary heart disease and periodontitis. In addition, periodontitis is the sixth major complication of diabetes mellitus. Some scholars divided the subjects into type 2 diabetes mellitus(T2DM) patients with moderate to severe periodontitis, patients with simple T2DM, patients with simple periodontitis and healthy control group. The blood lipid levels and HDL differences among the four groups were detected. It was found that periodontitis and diabetes mellitus interact with each other [35]; some scholars believe that periodontal pathogens can directly modify HDL and promote the development of type 2 diabetes. Other research results show that when coronary heart disease with T2DM, HDL particles are smaller, and the smaller HDL particles, the more coronary artery lesions in patients with smaller HDL particles. The size of HDL particles is only related to whether patients with coronary heart disease complicated with T2DM, but not with blood glucose control [36]. However, how to reconstruct HDL in CHD patients with T2DM and periodontitis needs further study.

4. Summary and Prospect

In conclusion, HDL can reduce periodontal inflammation and alveolar bone resorption through down regulating TLR4 Signal Transduction and NF -κB pathway by binding with LPS and inhibiting macrophages to regulate T cell-mediated cellular immune response. It is suggested that HDL is a promising adjunctive therapy for periodontitis, especially in the adjuvant treatment of systemic diseases with periodontitis such as diabetes mellitus with periodontitis, coronary heart disease with periodontitis and so on.