Systemic Chemical Desensitization of Peptidergic Sensory Neurons with Resiniferatoxin Inhibits Experimental Periodontitis

Background and objective: The immune system is an important player in the pathophysiology of periodontitis. The brain controls immune responses via neural and hormonal pathways, and brain-neuro-endocrine dysregulation may be a central determinant for pathogenesis. Our current knowledge also emphasizes the central role of sensory nerves. In line with this, we wanted to investigate how desensitization of peptidergic sensory neurons influences the progression of ligatureinduced periodontitis, and, furthermore, how selected cytokine and stress hormone responses to Gram-negative bacterial lipopolysaccharide (LPS) stimulation are affected. Material and methods: Resiniferatoxin (RTX; 50 μg/kg) or vehicle was injected subcutaneously on days 1, 2, and 3 in stress high responding and periodontitis-susceptible Fischer 344 rats. Periodontitis was induced 2 days thereafter. Progression of the disease was assessed after the ligatures had been in place for 20 days. Two h before decapitation all rats received LPS (150 μg/kg i.p.) to induce a robust immune and stress response. Results: Desensitization with RTX significantly reduced bone loss as measured by digital X-rays. LPS provoked a significantly higher increase in serum levels of the pro-inflammatory cytokine tumour necrosis factor (TNF)-, but lower serum levels of the anti-inflammatory cytokine interleukin (IL)-10 and the stress hormone corticosterone. Conclusions: In this model RTX-induced chemical desensitization of sensory peptidergic neurons attenuated ligatureinduced periodontitis and promoted a shift towards stronger pro-inflammatory cytokine and weaker stress hormone responses to LPS. The results may partly be explained by the attenuated transmission of immuno-inflammatory signals to the brain. In turn, this may weaken the anti-inflammatory brain-derived pathways

Calprotectin (S100A8/S100A9) and Myeloperoxidase: Co-Regulators of Formation of Reactive Oxygen Species

Inflammatory mediators trigger polymorphonuclear neutrophils (PMN) to produce reactive oxygen species (ROS: O2-, H2O2, ∙OH). Mediated by myeloperoxidase in PMN, HOCl is formed, detectable in a chemiluminescence (CL) assay. We have shown that the abundant cytosolic PMN protein calprotectin (S100A8/A9) similarly elicits CL in response to H2O2 in a cell-free system. Myeloperoxidase and calprotectin worked synergistically. Calprotectin-induced CL increased, whereas myeloperoxidase-triggered CL decreased with pH > 7.5. Myeloperoxidase needed NaCl for CL, calprotectin did not. 4-hydroxybenzoic acid, binding ∙OH, almost abrogated calprotectin CL, but moderately increased myeloperoxidase activity. The combination of native calprotectin, or recombinant S100A8/A9 proteins, with NaOCl markedly enhanced CL. NaOCl may be the synergistic link between myeloperoxidase and calprotectin. Surprisingly- and unexplained- at higher concentration of S100A9 the stimulation vanished, suggesting a switch from pro-oxidant to anti-oxidant function. We propose that the ∙OH is predominant in ROS production by calprotectin, a function not described before

Maternal deprivation of Lewis rat pups increases the severity of experimental periodontitis in adulthood

Background and Objective: Early life adverse events may influence susceptibility/resistance to chronic inflammatory diseases later in life by permanently dysregulating brain-controlled immune-regulatory systems. We have investigated the impact of infant-mother separation during early postnatal life on the severity of experimental periodontitis, as well as systemic stress and immune responses, in adulthood. Material and Methods: Pups of periodontitis resistant Lewis rats were separated from their mothers for 3 h daily during postnatal days 2-14 (termed maternal deprivation; MD), separated for 15 min daily during the same time period (termed handling; HD), or left undisturbed. As adults, their behaviour was tested in a novel stressful situation, and ligature-induced periodontitis applied for 21 days. Two h before sacrifice all rats were exposed to a gram-negative bacterial lipopolysaccharide (LPS) challenge to induce a robust immune and stress response. Results: Compared to undisturbed controls, MD rats developed significantly more periodontal bone loss as adults, whereas HD rats showed a tendency to less disease. MD and HD rats exhibited depression-like behaviour in a novel open field test, while MD rats showed higher glucocorticoid receptor (Gr) expression in the hippocampus, and HD rats had altered methylation of genes involved in the expression of hippocampal Gr. LPS provoked a significantly lower increase in circulating levels of the cytokine TGF-1β in MD and HD rats, but there were no significant differences in levels of the stress hormone corticosterone. Conclusion: Stressful environmental exposures in very early life may alter immune responses in a manner that influences susceptibility/resistance to periodontitis

Plasma Cytokine Profiles in Long-Term Strenuous Exercise

The open window theory indicates altered immunity 3 to 72 hours after exercise. The J-curve describes the risk of illness in response to exercise. The aim of this study was to examine the secretion of proinflammatory and anti-inflammatory cytokines before and after long-term strenuous exercise. Fourteen marathon and 16 half-marathon runners and 10 military cadets participating in a military ranger-training course were recruited to this study. Within-subject design was used measuring levels of plasma cytokines before, during, and after exercise. Plasma cytokines were measured using Luminex multiplex technology and ELISA. Comparing pre/post plasma levels both the marathon- and the half-marathon runners showed heavily increased levels of IL-6, IL-10, and IL-8 (P<0.001). LPS stimulation among the half-marathon runners decreased the postrace levels of IL-6, IL-1b, and TNFα by 45%, 24%, and 43%, respectively (P<0.01). During the ranger training course the spontaneous and LPS-stimulated levels of IL-6, IL-8, IL-10, IL-1b, and TNFα changed in a similar fashion as in the half-marathon runners although the fluctuations were smaller. Our study supports the open window and the J-curve theory; the immune system is more activated and the subjects are more threatened to infectious pathogens after intensive physical activity and in the period after exercise