Periodontitis Associates with a Type 1 IFN Signature in Peripheral Blood Neutrophils

Wright, Helen J.; Matthews, J. B.; Chapple, Iain L. C.; Ling-Mountford, Nic; Cooper, Paul R.

doi:10.4049/jimmunol.181.8.5775

Cited by 73 publications

(82 citation statements)

References 73 publications

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“…A similar pattern of neutrophil migration has been described in COPD where cells displayed poor migratory accuracy but with random movement in all directions at increased speed 72. Recent publications have also described compromised neutrophil bacterial phagocytosis in periodontitis86 (studies in COPD are less clear); enhanced neutrophil-derived ROS87,88 and increased NET formation in both COPD and periodontitis,89,90 all of which could contribute to the sustained inflammation that characterizes both the conditions 34,53. The cause for such injurious cell behavior is unclear, and it is unknown whether neutrophil dysfunction precedes or is a consequence of disease.…”

Section: Mechanismsmentioning

confidence: 56%

Is periodontitis a comorbidity of COPD or can associations be explained by shared risk factors/behaviors?

Hobbins¹,

Chapple

Sapey³

et al. 2017

COPD

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COPD is recognized as having a series of comorbidities potentially related to common inflammatory processes. Periodontitis is one of the most common human inflammatory diseases and has previously been associated with COPD in numerous observational studies. As periodontitis and COPD are both chronic, progressive conditions characterized by neutrophilic inflammation with subsequent proteolytic destruction of connective tissue, it has been proposed that they share common pathophysiological processes. The mechanisms proposed to link COPD and periodontitis include mechanical aspiration of oral contents into the respiratory tree, overspill of locally produced inflammatory mediators into the systemic circulation or oral or lung-derived bacteremia activating an acute-phase response and also reactive oxygen species (ROS) and cytokine release by systemic neutrophils at distant sites. Studies of systemic neutrophils in COPD and chronic periodontitis describe altered cellular functions that would predispose to inflammation and tissue destruction both in the lung and in the mouth, again potentially connecting these conditions. However, COPD and periodontitis also share risk factors such as age, chronic tobacco smoke exposure, and social deprivation that are not always considered in observational and interventional studies. Furthermore, studies reporting associations have often utilized differing definitions of both COPD and periodontitis. This article reviews the current available evidence supporting the hypothesis that COPD and inflammatory periodontal disease (periodontitis) could be pathologically associated, including a review of shared inflammatory mechanisms. It highlights the potential limitations of previous studies, in particular, the lack of uniformly applied case definitions for both COPD and periodontitis and poor recognition of shared risk factors. Understanding associations between these conditions may inform why patients with COPD suffer such a burden of comorbid illness and new therapeutic strategies for both the diseases. However, further research is needed to clarify factors that may be directly causal as opposed to confounding relationships.

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Section: Mechanismsmentioning

confidence: 56%

Is periodontitis a comorbidity of COPD or can associations be explained by shared risk factors/behaviors?

Hobbins¹,

Chapple

Sapey³

et al. 2017

COPD

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“…In a preliminary set of patients (n = 31) we identified the ISGs that account for the greatest variability in expression. These genes ( MX1 , ISG15 , IFIT1 , and IFIT3 ) are prototypical ISGs, previously shown to be highly expressed in stimulated neutrophils [66,68,69], lymphocytes [37], peripheral blood mononuclear cells [38,39], and whole blood [70]. Using a panel of three of these unrelated genes in a non-overlapping cohort (n = 120), we found that ARDS patients with ISG expression greater or less than one standard deviation from the mean had significantly worse clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Extremes of Interferon-Stimulated Gene Expression Associate with Worse Outcomes in the Acute Respiratory Distress Syndrome

et al. 2016

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Acute Respiratory Distress Syndrome (ARDS) severity may be influenced by heterogeneity of neutrophil activation. Interferon-stimulated genes (ISG) are a broad gene family induced by Type I interferons, often as a response to viral infections, which evokes extensive immunomodulation. We tested the hypothesis that over- or under-expression of immunomodulatory ISG by neutrophils is associated with worse clinical outcomes in patients with ARDS. Genome-wide transcriptional profiles of circulating neutrophils isolated from patients with sepsis-induced ARDS (n = 31) and healthy controls (n = 19) were used to characterize ISG expression. Hierarchical clustering of expression identified 3 distinct subject groups with Low, Mid and High ISG expression. ISG accounting for the greatest variability in expression were identified (MX1, IFIT1, and ISG15) and used to analyze a prospective cohort at the Colorado ARDS Network site. One hundred twenty ARDS patients from four urban hospitals were enrolled within 72 hours of initiation of mechanical ventilation. Circulating neutrophils were isolated from patients and expression of ISG determined by PCR. Samples were stratified by standard deviation from the mean into High (n = 21), Mid, (n = 82) or Low (n = 17) ISG expression. Clinical outcomes were compared between patients with High or Low ISG expression to those with Mid-range expression. At enrollment, there were no differences in age, gender, co-existing medical conditions, or type of physiologic injury between cohorts. After adjusting for age, race, gender and BMI, patients with either High or Low ISG expression had significantly worse clinical outcomes than those in the Mid for number of 28-day ventilator- and ICU-free days (P = 0.0006 and 0.0004), as well as 90-day mortality and 90-day home with unassisted breathing (P = 0.02 and 0.004). These findings suggest extremes of ISG expression by circulating neutrophils from ARDS patients recovered early in the syndrome are associated with poorer clinical outcomes.

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“…Post-treatment, DNA release was determined as above. No TNF-α priming was employed in this study, as peripheral blood neutrophils from periodontitis patients are already primed within the circulation by plasma cytokines (Wright et al ., 2008; Dias et al ., 2010). …”

Section: Methodsmentioning

confidence: 99%

Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals

et al. 2014

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Neutrophil extracellular traps (NETs) are a recently discovered addition to the defensive armamentarium of neutrophils, assisting in the immune response against rapidly dividing bacteria. Although older adults are more susceptible to such infections, no study has examined whether aging in humans influences NET formation. We report that TNF-α-primed neutrophils generate significantly more NETs than unprimed neutrophils and that lipopolysaccharide (LPS)- and interleukin-8 (IL-8)-induced NET formation exhibits a significant age-related decline. NET formation requires generation of reactive oxygen species (ROS), and this was also reduced in neutrophils from older donors identifying a mechanism for reduced NET formation. Expression of IL-8 receptors (CXCR1 and CXCR2) and the LPS receptor TLR4 was similar on neutrophils from young and old subjects, and neutrophils challenged with phorbol-12-myristate-13-acetate (PMA) showed no age-associated differences in ROS or NET production. Taken together, these data suggest a defect in proximal signalling underlies the age-related decline in NET and ROS generation. TNF-α priming involves signalling through p38 MAP kinase, but activation kinetics were comparable in neutrophils from young and old donors. In a clinical setting, we assessed the capacity of neutrophils from young and older patients with chronic periodontitis to generate NETs in response to PMA and hypochlorous acid (HOCL). Neutrophil extracellular trap generation to HOCL, but not PMA, was lower in older periodontitis patients but not in comparison with age-matched controls. Impaired NET formation is thus a novel defect of innate immunity in older adults but does not appear to contribute to the increased incidence of periodontitis in older adults.

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Periodontitis Associates with a Type 1 IFN Signature in Peripheral Blood Neutrophils

Cited by 73 publications

References 73 publications

Is periodontitis a comorbidity of COPD or can associations be explained by shared risk factors/behaviors?

Is periodontitis a comorbidity of COPD or can associations be explained by shared risk factors/behaviors?

Extremes of Interferon-Stimulated Gene Expression Associate with Worse Outcomes in the Acute Respiratory Distress Syndrome

Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals

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