Periodontitis develops through an inflammatory process caused by an infection at the microbial biofilm, followed by tissue destruction mediated by leukocytes, which cause clinically significant destruction of connective tissue and bone. Several elements derived from the bacteria cause the inflammatory response and the release of mediators involved in destruction of the periodontium. There are number of inflammatory mediators released by leukocytes, mainly neutrophils, upon bacterial challenge. Neutrophils produce and release eosinophil cationic protein (ECP) and histamine, two important inflammatory mediators; however, their role has not been characterized in periodontal inflammation. Thus, the purpose of this study is to investigate whether neutrophils from patients with periodontitis can produce ECP and histamine in response to lipopolysaccharides (LPSs).

Methods

ECP and histamine production in response to LPSs was analyzed by enzyme-linked immunosorbent assay. Expression of the histidine decarboxylase and ECP was also analyzed by flow cytometry and fluorescence microscopy in neutrophils from patients with periodontitis in response to LPS.

Results

It was found that neutrophils from patients with periodontitis express higher levels of histidine decarboxylase and ECP than those from healthy volunteers, and they also release higher levels of histamine.

Conclusion

Findings described could represent new knowledge indicating neutrophils as a source of histamine and ECP in the progression of periodontitis.

According to studies of pathologic periodontal processes in general, and those of periodontitis in particular, there are sufficient indications to consider these processes to be an incapacity of neutrophils to adequately defend the host. The authors have previously described, to the best of their knowledge, for the first time, that eosinophil cationic protein (ECP) and histamine are produced by human neutrophils.2, 3 Simultaneously, the authors have shown how these cells synthesize and release both inflammatory mediators upon stimulation by several types of neutrophil agonists, including lipopolysaccharide (LPS).2, 3

ECP is a small, basic protein found in the matrix of eosinophil secondary granules and exhibits cytotoxic, heminthotoxic, and ribonuclease activity.4-6 In addition, ECP also has functions that are not dependent on its cytotoxicity, such as its participation in the functions of the complement coagulation and fibrinolysis. ECP also exhibits numerous modulatory effects, including suppression of T cell proliferation, upregulation of immunoglobulin synthesis by B cells, mast cell degranulation, and stimulation of mucus secretion in the airway.7-11

Histamine has been established to play a pathophysiologic regulatory role in various immunologic reactions. Histamine is a diamine derivate of histidine that is produced under the control of a single enzyme, histidine decarboxylase (HDC).12-14 The authors previously found that neutrophils from patients who were allergic have higher levels of HDC expression than those from healthy volunteers.2, 3 In addition, neutrophils from patients who were allergic can be primed for specific stimuli.2, 3 The term “priming” has been used since the early 1980s to describe the ability of a primary agent to enhance the magnitude of the oxidative response of phagocytic cells to a second stimulus.15 The resting state exists in circulating blood neutrophils, whereas the primed state is induced in neutrophils upon exposure to diverse “priming” stimuli, such as proinflammatory cytokines, bacteria-derived products, as well as the adhesion process itself.15 Immunocytochemical analyses of inflamed periodontal tissues have also confirmed the presence of large numbers of recruited neutrophils in diseased tissue in vivo.16 Neutrophils are considered central to the pathogenesis of chronic periodontitis (CP), having the potential to result in collateral periodontal host tissue damage.16 For this reason, the priming of neutrophils may have a critical role in the progression of periodontitis.16 The purpose of this study is to characterize this process.

1 MATERIALS AND METHODS

1.1 Materials

Endotoxin levels in all reagents used in this work were measured by a Limulus lysate assay1 and were ≤0.01 ng/mL. Viability of cells was verified using the trypan blue dye exclusion test.

1.2 Patients and controls

This study included 35 Spanish participants (21 males and 14 females) from Seville, Spain (Table 1). The clinical history of all patients participating in the study was recorded (personal data and medical history). All patients are classified as having generalized CP corresponding to Type IIb, according to the International Workshop (1999),17 with > 30% of affected locations, the severity being mild to moderate, i.e. with insertion losses of 2 to 4 mm (Tables 2 and 3). The ethics committee of Macarena Hospital, Seville, Spain approved the study, and each participant provided written informed consent.

Table 1. Demographic characteristics of study patients

Characteristic	Healthy volunteers	Patients with periodontitis
Caucasian	All	All
Males, n	6	15
Females, n	4	10
Age (years), mean ± SEM	50 ± 3.2	54.7 ± 1.9
Smokers	None	All

Table 2. Clinical characteristics (mean ± SEM) of study patients

Parameter	Healthy volunteers	Patients with periodontitis	P Value
Plaque index	18.9 ± 13.36	83.46 ± 32.08	0.001
Probing depth	1.85 ± 0.3	3.82 ± 0.75	<0.001
Gingival bleeding	10.37 ± 4.93	64.57	<0.001
Gingival recession	0.4 ± 0.3	0.97 ± 0.8	<0.001

Table 3. Culture of GCF bacterial flora (CFU/mL, mean ± SEM)

	Healthy volunteers	Patients with periodontitis	P Value
Bacterial flora	4.1 ± 3.7 × 10⁵	1.91 ± 1.2 × 10⁷	0.002
Aa	1.94 ± 6.41 × 10³	6.81 ± 1.82 × 10⁵	0.30
Pg	5.9 ± 8.3 × 10³	6.7 ± 8.4 × 10⁷	<0.001
Pi	6.2 ± 1.21 × 10⁴	6 ± 8.4 × 10⁶	<0.001
Tf	9.31 ± 1.92 × 10³	7.5 ± 1.42 × 10⁶	<0.001
Pm	1.21 ± 3.42 × 10³	3.81 ± 1.4 × 10⁴	0.40
Fn	2.51 ± 2.8 × 10³	2.71 ± 4.45 × 10⁵	<0.001
Capn	9.2 ± 3.1 × 10²	2.82 ± 6.5 × 10³	0.5
Ec	1.91 ± 4.2 × 10³	6.8 ± 1.93 × 10³	0.70

GCF = gingival crevicular fluid; CFU = colony-forming unit; Aa = Aggregatibacter actinomycetemcomitans; Pg = Porphyromonas gingivalis; Pi = Prevotella intermedia; Tf = Tannerella forsythia; Pm = Parvimonas micra; Fn = Fusobacterium nucleatum; Capn = Capnocytophaga; Ec = Eikenella corrodens.

1.3 Cell isolation

Highly purified human neutrophils (on average > 99%) were purified as previously described.2

1.4 Analysis of total and released histamine

Neutrophils were cultured with LPS2 (1 μg/mL) as previously described.3 Histamine was measured in the culture supernatant or the cellular pellets using an enzyme-linked immunosorbent assay (ELISA) histamine kit3 following instructions provided by the manufacturer.

1.5 Analysis of HDC and ECP by flow cytometry

Analysis of HDC and ECP expression by flow cytometry was performed as previously described.2, 3

1.6 Analysis of HDC and ECP by immunostaining

The analysis of the HDC and ECP expression by immunostaining was performed as previously described.2, 3

1.7 Neutrophil culture for ECP release

Neutrophils were cultured as previously described.2

1.8 Statistical analyses

Values are expressed as mean ± standard error of the mean (SEM). Comparison between two groups was performed using the student t test and le two groups were compared by analysis of variance. P ≤0.05 was considered statistically significant.

2 RESULTS

2.1 LPS induces ECP release by neutrophils from patients with periodontitis and healthy volunteers

The potential ability to release ECP into the culture medium of neutrophils from healthy volunteers and patients with periodontitis stimulated with LPS was evaluated. Figure 1A shows that LPS triggered ECP release from both healthy volunteers and patients with periodontitis. However, the release was significantly higher in neutrophils from patients with periodontitis than those from healthy volunteers.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Periodontitis influences levels of LPS-induced ECP production by neutrophils. A) Neutrophils from patients with periodontitis and healthy volunteers were incubated with LPS (1 μg/mL) for 18 hours, and levels of ECP in the culture medium supernatants were determined using an enzyme immunoassay. Values shown are the mean ± SEM from seven independent assays in which each measurement was performed in duplicate. B) Intracellular ECP and cell surface CD66b expression was subsequently analyzed by flow cytometry in neutrophils from patients with periodontitis. Results from a representative experiment of three with similar findings are shown. Numbers to the right of each plot represent the percent of double-positive cells (CD66b⁺/ECP⁺). C) Neutrophils from a patient with periodontitis and a healthy volunteer were processed as indicated in the Materials and Methods section for light microscopy (left column) or intracellular ECP detection by fluorescence microscopy (right column). Two separate experiments were performed with similar results

2.2 Intracellular ECP expression by human neutrophils

Next, analysis was made of intracellular ECP expression by flow cytometry. It was observed that a lower proportion of healthy volunteers had ECP⁺/CD66b⁺ cells than patients with periodontitis (Fig. 1B). The same results were obtained using immunofluorescence staining (Fig. 1C). Immunofluorescence experiments were performed in seven patients and three healthy donors, twice per patient.

2.3 HDC expression differs in neutrophils from patients with periodontitis and healthy volunteers

A representative comparison of the studied groups is shown in Figure 2A. Ninety-eight percent of neutrophils (CD66b⁺) from patients with periodontitis were positive for HDC compared with the 10% of neutrophils from healthy volunteers. Flow cytometry experiments were performed in all patients and all healthy volunteers. Analysis by immunofluorescence showed similar results (Fig. 2B). Immunofluorescence experiments were performed in seven patients and three healthy donors, twice per participant.

2.4 Histamine release by human neutrophils

An analysis was performed of the capacity of neutrophils to release histamine after being stimulated by LPS, thereby indicating the activity of the HDC. This release of histamine in the cultured supernatant was performed using ELISA, and production of histamine was greater in neutrophils from patients with periodontitis than in neutrophils from healthy volunteers (Fig. 2C).

3 DISCUSSION

Previous reports have shown that neutrophils from patients with periodontitis behave differently after challenge with LPS and other stimuli than those from healthy donors.18-20 However, in this study it has been shown for the first time, to the best knowledge of the authors, that neutrophils from patients with periodontitis have higher levels of HDC and produce higher levels of histamine than those from healthy volunteers. In addition, the same pattern was observed for ECP expression.

Number of eosinophils can be associated with parameters of periodontitis in adolescents.21 There are data indicating that there are elevated eosinophil counts and ECP production in stored and secretory forms in gingival crevicular fluid (GCF) from patients with periodontitis, compared with levels in venous blood.22 Eosinophil counts were found to be elevated in the gingival microvascular blood of patients with periodontitis.23 Eosinophils are cells that intervene in inflammatory processes, especially chronic inflammatory processes, by releasing different substances that cause tissue damage that can be enough to cause a lesion to the target organ.7-9

ECP is a small cationic protein found in eosinophil secondary granules that exhibits cytotoxic, heminthotoxic, and ribonuclease activity.4-6 In addition, ECP also has functions independent of its cytotoxicity, such as its involvement in complement coagulation and fibrinolysis. ECP also exhibits numerous modulatory effects, including suppression of T cell proliferation, augmentation of immunoglobulin synthesis by B cells, mast cell degranulation, and stimulation of mucus secretion in the airway.7-11

ECP is active against different strains of bacteria by means of its action in both the cell wall and cytoplasmic membrane.7-9 ECP is able to modulate the inflammatory process that induces periodontitis. Thus, evidence is increasing about the important role of neutrophils in periodontitis. CP is a model of tissue destruction mediated by the proinflammatory neutrophil response.24-26 Peripheral blood neutrophils from patients with periodontitis have a high response in the production of reactive oxygen species.27 A successful treatment therapy reverts this process.27 Neutrophils are considered central to the pathogenesis of CP, with the potential to result in collateral periodontal host tissue damage.

Neutrophils are the most abundant leukocytes in human circulation.28 In the steady state, circulating neutrophils flow freely in blood vessels and seek out signs of infection and inflammation. Once inflammation occurs, the active state is found in neutrophils at inflammatory or infection sites where the recruited neutrophils directly contact pathogens or injury signals.29 However, under steady-state conditions, circulating neutrophils remain in a resting state and exhibit low antimicrobial activity. Before encountering pathogens at an inflammatory site, neutrophils need to be “primed” to gain an enhanced bactericidal capacity during their recruitment process. Thereafter, upon subsequent exposure to the pathogens, the primed neutrophils become “activated” and exhibit robust bactericidal activity.30 In general, “priming” refers to a process by which a prior exposure to a primary agonist potentiates the action of a posterior agonist31 such as proinflammatory cytokines, chemoattractants, or bacteria-derived products, as well as by the adhesion process itself.32 Phosphorylation and translocation of the nicotinamide adenine dinucleotide phosphate oxidase components have been proposed as essential events for neutrophil priming.30 Upon exposure to priming agents, neutrophils rapidly display dramatic functional changes, including enhanced phagocytosis, robust respiratory burst, and changes in expression levels of surface molecules.31 All of these effects greatly contribute to neutrophil antimicrobial functions in inflamed tissues. Thus, priming represents a key process regulating the functional responsiveness of neutrophils. Immunocytochemical analyses of inflamed periodontal tissues have also confirmed the presence of large numbers of recruited neutrophils in diseased tissue in vivo.33 Neutrophils are considered central to the pathogenesis of CP, having the potential to result in collateral periodontal host tissue damage.33 Thus, in this study, it has been shown for the first time, to the best knowledge of the authors, that neutrophils from patients with periodontitis are able to produce and release histamine and ECP in higher levels than those from healthy volunteers.

Histamine, a potent bioamine with multiple activities in various pathologic and physiologic conditions, was recognized as an inflammatory mediator released by several cells.34-40 There is increasing evidence about the participation of histamine in the progress of periodontitis. Several studies have shown that therapeutic administration of antihistamines improves clinical symptoms of periodontitis.41-47

4 CONCLUSIONS

It was found that neutrophils from patients with periodontitis express higher levels of HDC and ECP than those from healthy volunteers, and they also release higher levels of histamine. The findings described could represent new knowledge of neutrophils as a source of histamine and ECP in the progression of periodontitis.

ACKNOWLEDGMENTS

This work was supported by grants from the Regional Government of Andalusia (Grants for Research Groups), Seville, Spain; FIS-RETIC Asthma, Adverse and Allergic reactions (ARADyAL) (RD16/0006); and Alergol Fundation, Seville, Spain. The authors would like to thank Antonio Vega-Rioja for the critical reading and English correction of the manuscript. The authors report no conflicts of interest related to this study.

1 Chromogenix Coatest, Instrumentation Laboratory, Bedford, MA.

2 Lonza, Verviers, Belgium.

3 Chromogenix, Instrumentation Laboratory.

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Citing Literature

Volume89, Issue2

February 2018

Pages 228-234

Eosinophil cationic protein and histamine production by neutrophils from patients with periodontitis

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References

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