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Neutrophil Hyper-responsiveness in Periodontitis

Periodontal Research Group, School of Dentistry, University of Birmingham, St Chad’s Queensway, Birmingham B4 6NN, UK

Correspondence: ^* corresponding author, j.b.matthews{at}bham.ac.uk

	ABSTRACT

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Peripheral neutrophil hyper-responsiveness in chronic periodontitis leads to excessive reactive oxygen species (ROS) production. We aimed to determine whether neutrophil hyper-responsiveness was constitutive or reactive, and to discover the effect of non-surgical therapy. Peripheral blood neutrophils from patients (n = 19), before and 3 months after therapy, and matched control individuals were Fc-receptor-stimulated with/without priming with P. gingivalis and F. nucleatum. Total and extracellular ROS were determined by luminol/isoluminol chemiluminescence. The high total ROS generation of patients’ neutrophils compared with that of control individuals (P = 0.016) continued at a reduced level post-therapy (P = 0.059). Reduced activity post-therapy was also seen with priming. Unstimulated total ROS levels did not differ between patients and control individuals before or after therapy. However, the high unstimulated, extracellular ROS production by patients’ neutrophils compared with control individuals (P < 0.05) continued post-therapy and was unaffected by priming. Therapy reduced Fc-receptor-stimulated total ROS production, but not unstimulated extracellular radical release, suggesting that constitutive and reactive mechanisms underlie neutrophil hyper-responsiveness.

Key Words: chronic periodontitis • neutrophil hyper-responsiveness • therapy • Fc-receptor • ROS

	INTRODUCTION

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Neutrophil-mediated oxidant injury is a feature of many inflammatory diseases (Morel et al., 1991; Noguera et al., 2001). Recent studies have suggested that peripheral blood neutrophils of persons with localized aggressive periodontitis are hyper-responsive with respect to reactive oxygen species (ROS) generation, due to reduced gene and protein expression of diacylglycerol (DAG) kinase (Gronert et al., 2004), inhibition of which is known to amplify the respiratory burst in normal neutrophils (Topham and Prescott, 1999).

Current evidence indicates that chronic periodontitis occurs in predisposed individuals who have an abnormal inflammatory/immune response to the subgingival plaque biofilm at the gingival margin (Page and Kornman, 1997; Socransky et al., 1998). Over the last two decades, a body of evidence has accumulated that peripheral blood neutrophils from persons with chronic periodontitis generate significantly higher levels of ROS after in vitro Fc-receptor (FcR) stimulation, compared with age- and gender-matched periodontally healthy control individuals (Chapple and Matthews, 2007). Furthermore, we have recently shown that peripheral neutrophils from persons with chronic periodontitis, in the absence of exogenous stimulation, show an increase in extracellular ROS release in vitro (Matthews et al., 2007). The underlying basis for this hyper-responsive neutrophil phenotype in chronic periodontitis is unclear, and has not been shown to be associated with altered expression of DAG kinase (Gronert et al., 2004), adhesion molecules (Gustafsson and Åsman, 1996) or phox genes (Matthews et al., 2007), FcR polymorphisms (Kobayashi et al., 1997; Fredriksson et al., 2003), the method of neutrophil preparation (Fredriksson et al., 1999), or in vitro priming with TNF, E. coli LPS, fMetLeuPhe, or ArgGlyAspSer (Gustafsson et al., 1997; Fredriksson et al., 1998). However, recent evidence suggests that oxidative stress is an important factor in local tissue damage in chronic periodontitis (Sugano et al., 2000; Takane et al., 2002; Sculley and Langley-Evans, 2003; Panjamurthy et al., 2005).

This proposed hyper-responsive neutrophil phenotype in chronic periodontitis might be an innate property of neutrophils (i.e., constitutive), or involve a functional sensitization or priming by cytokines or bacterial components. Peripheral priming may also have a constitutive element, and therefore represent a risk factor for periodontitis, or merely reflect heightened levels of peripheral cytokines or bacterial components resulting from the disease process. Analysis of data published to date suggests that FcR-stimulated neutrophil hyper-responsiveness is constitutive, because it can be detected in cross-sectional studies comparing cells isolated from persons successfully treated and those from age- and gender-matched periodontally healthy control individuals (Fredriksson et al., 1998, 2003). However, currently, there are no data from definitive longitudinal intervention studies analyzing the impact of therapeutic reductions in periodontal inflammation upon neutrophil hyper-responsivity.

To investigate whether the hyper-responsive neutrophil phenotype is a constitutive feature of persons with periodontitis or a reactive response to periodontal pathogens, we performed a longitudinal intervention study to determine the effects of successful periodontal therapy on ROS production (extracellular and total) by unstimulated and FcR-stimulated peripheral blood neutrophils. We included experiments with and without priming with a mixture of two putative periodontal pathogens (Porphyromonas gingivalis and Fusobacterium nucleatum) (Kolenbrander et al., 1995; Socransky et al., 1998), to determine whether peripheral stimulation with bacterial components might play a role in the observed neutrophil hyper-responsive phenotype in periodontitis.

	MATERIALS & METHODS

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Patients
Individuals with chronic periodontitis (n = 19; age range = 36–61 yrs) were recruited from patients referred to the periodontal department at Birmingham Dental Hospital. Chronic periodontitis was defined as previously described (Brock et al., 2004). Age- and gender-matched periodontally healthy control individuals (n = 19; age range = 37–62 yrs; five male, 14 female) were recruited from staff of the Dental Hospital. All study participants were systemically healthy. Exclusion criteria included pregnancy, diabetes, use of non-steroidal anti-inflammatory or antimicrobial drugs, mouthwashes, or vitamin supplements within the previous 3 mos. All volunteers were never-smokers, did not use recreational drugs, and had no special dietary requirements. Ethical approval was granted by the South Birmingham Local Research Ethics Committee (LREC 5643). After providing informed consent, study participants completed a medical questionnaire.

Collection of Venous Blood and Preparation of Neutrophils
Heparinized (17 IU/mL) venous blood was obtained from 19 persons with periodontitis and from age-/gender-matched control individuals before (Baseline) and 3 mos after conventional non-surgical therapy (Review). Blood was obtained from a patient and a matched control individual within 30 min of each other. Two aliquots of blood were obtained from each participant; one was sent for routine differential blood count, and the other was used for neutrophil preparation. Neutrophils were isolated with the use of a discontinuous Percoll gradient ( = 1.079:1.098), followed by erythrocyte lysis (0.83% NH₄Cl containing 1% KHCO₃, 0.04% Na₂EDTA.2H₂O and 0.25% bovine serum albumin; 20 min). Isolated cells were washed and re-suspended at 1 x 10⁶ cells/mL in PBS supplemented with glucose (1 mM) and cations (1 mM MgCl₂, 1.5 mM CaCl₂). Cell viability was determined immediately prior to assay by trypan blue exclusion and was typically > 98%.

Periodontal Assessment
Clinical measures were recorded by a single examiner at baseline and 3 mos post-therapy, and included probing pocket depth (PPD), recession, clinical attachment loss (CAL, by summation of PPD and recession), dichotomous measures for percent sites bleeding on marginal probing (%BOP), and percentage sites with plaque (%PLQ). Probing measures were performed in duplicate (or triplicate if differences 1 mm existed), by means of a UNC-PCP15 probe (Hu-Friedy, Chicago, IL, USA), and the mean pocket depth per site was calculated from the two closest (from triplicate) probing measures. Clinical data were double-entered into a spreadsheet (Microsoft Excel, Windows XP), and means of patient means were calculated as the "per patient" value for baseline and post-therapy measures.

Thirty-second gingival crevicular fluid samples were collected by means of Periopaper^TM strips (Oraflow, Inc., Smithtown, NY, USA) (Brock et al., 2004), 1 wk after clinical measures, from mesio-buccal sites of teeth exhibiting the deepest pockets. Volumes were measured by means of a pre-calibrated Periotron 8000^TM (Oraflow, Inc., Smithtown, NY, USA) (Chapple et al., 1999).

Non-surgical Therapy
One operator provided quadrant scaling/root planing (4 visits within 4–6 wks) using slimline ultrasonic scaler inserts (Cavitron, Dentsply, Weybridge, Surrey, UK) and Gracey curettes (LM Dental, Turku, Finland). Teeth were debrided until deemed free of detectable deposits.

Bacterial Culture and Suspensions
Staphylococcus aureus (NCTC 6571) was grown in air on mannitol salt agar and inoculated into tryptone soy broth. Fusobacterium nucleatum (Fn; ATCC 10953) and Porphyromonas gingivalis (Pg; ATCC 33277) were grown anaerobically at 37°C as previously described (Roberts et al., 2002). Bacteria were washed 3 times in sterile PBS, and heat-treated (100°C for 10 min) prior to dilution with sterile PBS to give a final suspension of 5 x 10⁹ cells/mL, which was stored at –80°C. Opsonized S. aureus was prepared as previously described (Bergstrom and Åsman, 1993) and stored as a 1.2 x 10⁹cells/mL suspension at –80°C.

Enhanced Chemiluminescent Assay for ROS
Chemiluminescence assays were performed with luminol, to detect total radical generation (intra- and extracellular), and isoluminol, to detect extracellular radical production. All assays were performed (37°C) with a Berthold microplate-luminometer (LB96v, EG and G Berthold UK Ltd., Milton Keynes, Bucks, UK), essentially as described previously (Matthews et al., 2007). The lower limits of detection (mean RLU of reagent blank plus 3 standard deviations) for the luminol and isoluminol assays with this instrument and our experimental protocols are 17.1 RLU/sec and 14.6 RLU/sec, respectively. A 35-µL quantity of supplemented PBS, 30 µL of luminol (3 mmol/L), or 60 µL of isoluminol (3 mmol/L) with 6U horseradish peroxidase was added to pre-blocked (PBS containing 1% BSA, overnight, 4°C) white microwells (Immunolon2, Dynex, Chantilly, VA, USA). The plate was placed into the luminometer (37°C), and 10 µL of PBS or Pg/Fn mixture (equivalent to 0.75 Pg + 1.5 Fn per neutrophil) and 100 µL of isolated cells were added to each well; light output was monitored for 30 min. Cells were then stimulated with 25 µL opsonized S. aureus (300 bacteria/neutrophil) in PBS or 25 µL PBS for the unstimulated wells. All samples were run in triplicate within 2 hrs of blood collection, with samples from paired patients and control individuals analyzed at the same time. Light emission in relative light units (RLU/sec) was recorded during the 30-minute pre-stimulation period, for the study of baseline, unstimulated radical release and after stimulation for 150 min. Peak RLUs were determined for both pre- and post-stimulation incubation periods.

The priming dose of Pg/Fn was determined from preliminary experiments on normal neutrophils, and was found to generate increased FcR-mediated luminol-dependent chemiluminescence without stimulating significant ROS alone.

Data Handling and Statistical Analysis
Chemiluminescent data were recorded automatically into Microsoft Excel. Data were manipulated in Excel, and statistical evaluation was performed with Minitab (ver. 14, Minitab Ltd., Coventry, W. Midlands, UK). The Wilcoxon rank-sum test (one-tailed) was used for all statistical comparisons. A level of P < 0.05 was used for assigning statistical significance.

	RESULTS

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Longitudinal Changes in Clinical Measures
The success of non-surgical therapy was confirmed by improvements in all clinical measures at the three-month review (Table 1; P 0.001 for all parameters). These were largely consistent with reports in the wider literature for patients with mild to moderate periodontitis (Cobb, 1996). There were no differences in differential blood counts between patients and control individuals, or between samples taken from donors over the three-month study period (data not shown).

Extracellular (Isoluminol-dependent) Radical Production by Neutrophils
Extracellular radical production by FcR-stimulated neutrophils was approximately 6–7% of total generation detected by luminol, and there were no significant differences between neutrophils from patients and control individuals, regardless of priming with Pg/Fn (Table 3). Unstimulated radical release by neutrophils was significantly lower than that generated after FcR-stimulation (P < 0.001). In the absence of stimulation, patients’ cells produced significantly higher chemiluminescent signals than those from control individuals, both pre- (P = 0.01) and post-therapy (P = 0.023; Table 3). Priming with Pg/Fn had little effect on unstimulated extracellular radical-generation, with patients’ cells generating greater chemiluminescence than control cells, pre- (P = 0.047) and post-therapy (P = 0.049).

	DISCUSSION

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Analysis of the data presented demonstrates that the well-characterized hyper-reactive neutrophil phenotype relative to total radical production after FcR-stimulation is reduced, but not removed, by effective non-surgical therapy. This result extends the results of previous cross-sectional studies comparing successfully treated patients with periodontally healthy control individuals, where FcR-mediated neutrophil hyper-reactivity has been detected to various degrees of significance (P = 0.0083, Fredriksson et al., 2003; P = 0.06, Gustafsson et al., 2006). The ability to detect hyper-reactivity in the earlier study (Fredriksson et al., 2003) was shown to be highly dependent upon the absence of Ca⁺⁺, the addition of which reduced the difference between patients and control individuals to a level that just reached statistical significance (P = 0.0468). Despite this, these studies appear to provide evidence that this hyper-reactive phenotype is a constitutive feature of persons with periodontitis.

All our experiments were performed in the presence of divalent cations (Mg⁺⁺, Ca⁺⁺) and glucose, in an attempt to reflect more accurately the in vivo situation. Analysis of our data indicates a more complex picture, and the results obtained after priming neutrophils with a mixture of whole P. gingivalis and F. nucleatum do not support an entirely constitutive basis for the FcR-mediated neutrophil hyper-reactivity. Priming with Pg/Fn reduced the heightened FcR-stimulated oxygen radical production by patient neutrophils at baseline, before therapy, and completely removed it post-therapy. Analysis of our data, taken together, suggests that peripheral priming with components of Pg/Fn and other unknown factors (e.g., cytokines) are the major contributors to the FcR-mediated neutrophil hyper-reactivity detected in chronic periodontitis patients.

There is support for the idea that peripheral priming by cytokines, reversible by successful therapy, could be a factor in FcR-mediated neutrophil hyper-reactivity in chronic periodontitis. Thus, alterations of plasma levels of cytokines have been reported after successful therapy in cases of rapidly progressive disease (IL-8) (Gainet et al., 1998), and after full-mouth extractions (IL-8, MCP-1) (Fokkema et al., 2003).

A previous study has suggested that peripheral blood neutrophils from successfully treated patients exhibit FcR-mediated hyper-reactivity in terms of production of extracellular oxygen radicals (Fredriksson et al., 2003). Although mean and median levels of extracellular radicals generated by patients’ cells were greater than from those of control individuals before and after therapy, the differences found here were not statistically significant. Interestingly, the effect of Pg/Fn priming removed this observed difference.

Recently, we have reported that peripheral blood neutrophils from chronic periodontitis patients exhibited increased release of extracellular radicals in the absence of stimulation, compared with those from periodontally healthy control individuals (Matthews et al., 2007). The results presented here demonstrate that this baseline, unstimulated hyper-activity is not altered by successful therapy, and is maintained after cells are primed with Pg/Fn. While the levels of radical release are small, analysis of these data clearly indicates that this baseline, unstimulated hyper-activity is constitutive in nature and could represent a risk factor for the development and progression of periodontitis. Such low-level extracellular radical release is likely to contribute substantially to periodontal tissue damage only if it is associated either with increased neutrophil-trafficking into the periodontal tissues, decreased/altered neutrophil apoptosis, and/or altered anti-oxidant status. Lowered local and peripheral anti-oxidant status has been demonstrated in persons with periodontitis (Brock et al., 2004; Chapple et al., 2007), and might make the small extracellular radical generation detected in vitro of significance in vivo.

The role of neutrophil hyper-responsiveness in the generation of tissue damage in periodontitis has been recognized for over a decade, but it is only recently that evidence has been forthcoming confirming the presence of oxidative stress in periodontal tissues (Sugano et al., 2000; Takane et al., 2002; Sculley and Langley-Evans, 2003; Panjamurthy et al., 2005). Analysis of our data suggests a dual role for neutrophils in the production of oxidative tissue damage, involving a potentially reversible FcR-mediated hyper-reactivity and a constitutional hyper-activity relative to baseline oxygen radical release. One can speculate that the former is important in disease progression, whereas the latter is an important etiological risk factor.

	ACKNOWLEDGMENTS

 
This work was supported by the Medical Research Council UK (grant no. G0000797).

Received for publication November 1, 2006. Revision received February 20, 2007. Accepted for publication April 3, 2007.

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Journal of Dental Research, Vol. 86, No. 8, 718-722 (2007)
DOI: 10.1177/154405910708600806


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