Summary
Neutrophils are of key importance in periodontal health and disease. In their absence or when they are functionally defective, as occurs in certain congenital disorders, affected individuals ...develop severe forms of periodontitis in early age. These observations imply that the presence of immune‐competent neutrophils is essential to homeostasis. However, the presence of supernumerary or hyper‐responsive neutrophils, either because of systemic priming or innate immune training, leads to imbalanced host–microbe interactions in the periodontium that culminate in dysbiosis and inflammatory tissue breakdown. These disease‐provoking imbalanced interactions are further exacerbated by periodontal pathogens capable of subverting neutrophil responses to their microbial community's benefit and the host's detriment. This review attempts a synthesis of these findings for an integrated view of the neutrophils' ambivalent role in periodontal disease and, moreover, discusses how some of these concepts underpin the development of novel therapeutic approaches to treat periodontal disease.
Summary
Neutrophils are a major component of the innate host response, and the outcome of the interaction between the oral microbiota and neutrophils is a key determinant of oral health status. The ...composition of the oral microbiome is very complex and different in health and disease. Neutrophils are constantly recruited to the oral cavity, and their protective role is highlighted in cases where their number or functional responses are impeded, resulting in different forms of periodontal disease. Periodontitis, one of the more severe and irreversible forms of periodontal disease, is a microbial‐induced chronic inflammatory disease that affects the gingival tissues supporting the tooth. This chronic inflammatory disease is the result of a shift of the oral bacterial symbiotic community to a dysbiotic more complex community. Chronic inflammatory infectious diseases such as periodontitis can occur because the pathogens are able to evade or disable the innate immune system. In this review, we discuss how human neutrophils interact with both the symbiotic and the dysbiotic oral community; an understanding of which is essential to increase our knowledge of the periodontal disease process.
Exposure to pro-inflammatory cytokines, chemokines, mitochondrial contents, and bacterial and viral products induces neutrophils to transition from a basal state into a primed one, which is currently ...defined as an enhanced response to activating stimuli. Although, typically associated with enhanced generation of reactive oxygen species (ROS) by the NADPH oxidase, primed neutrophils show enhanced responsiveness of exocytosis, NET formation, and chemotaxis. Phenotypic changes associated with priming also include activation of a subset of functions, including adhesion, transcription, metabolism, and rate of apoptosis. This review summarizes the breadth of phenotypic changes associated with priming and reviews current knowledge of the molecular mechanisms behind those changes. We conclude that the current definition of priming is too restrictive. Priming represents a combination of enhanced responsiveness and activated functions that regulate both adaptive and innate immune responses.
Neutrophils are phagocytic innate immune cells essential for killing bacteria via activation of a wide variety of effector responses and generation of large amounts of reactive oxygen species (ROS). ...Majority of the ROS in neutrophils is generated by activation of the superoxide‐generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Independent of their anti‐microbial function, NADPH oxidase‐derived ROS have emerged as key regulators of host immune responses and neutrophilic inflammation. Data from patients with inherited defects in the NADPH oxidase subunit alleles that ablate its enzyme function as well as mouse models demonstrate profound dysregulation of host inflammatory responses, neutrophil hyper‐activation and tissue damage in response to microbial ligands or tissue trauma. A large body of literature now demonstrates how oxidants function as essential signaling molecules that are essential for the regulation of neutrophil responses during priming, degranulation, neutrophil extracellular trap formation, and apoptosis, independent of their role in microbial killing. In this review we summarize how NADPH oxidase‐derived oxidants modulate neutrophil function in a cell intrinsic manner and regulate host inflammatory responses. In addition, we summarize studies that have elucidated possible roles of oxidants in neutrophilic responses within the oral mucosa and periodontal disease.
Activation of neutrophil NADPH oxidase (NOX2) enzyme complex generates reactive oxygen species (ROS). ROS generated play critical roles in the activation and redox modulation of neutrophil antimicrobial capacity and effector functions.
Periodontitis is an irreversible, chronic inflammatory disease where inflammophilic pathogenic microbial communities accumulate in the gingival crevice. Neutrophils are a major component of the ...innate host response against bacterial challenge, and under homeostatic conditions, their microbicidal functions typically protect the host against periodontitis. However, a number of periodontal pathogens developed survival strategies to evade neutrophil microbicidal functions while promoting inflammation, which provides a source of nutrients for bacterial growth. Research on periodontal pathogens has largely focused on a few established species: Tannerella forsythia, Treponema denticola, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans, and Porphyromonas gingivalis. However, advances in culture‐independent techniques have facilitated the identification of new bacterial species in periodontal lesions, such as the two Gram‐positive anaerobes, Filifactor alocis and Peptoanaerobacter stomatis, whose characterization of pathogenic potential has not been fully described. Additionally, there is not a full understanding of the pathogenic mechanisms used against neutrophils by organisms that are abundant in periodontal lesions. This presents a substantial barrier to the development of new approaches to prevent or ameliorate the disease. In this review, we first summarize the neutrophil functions affected by the established periodontal pathogens listed above, denoting unknown areas that still merit a closer look. Then, we review the literature on neutrophil functions and the emerging periodontal pathogens, F. alocis and P. stomatis, comparing the effects of the emerging microbes to that of established pathogens, and speculate on the contribution of these putative pathogens to the progression of periodontal disease.
Neutrophils normally play a critical role in maintaining homeostasis in the oral cavity, but both established and emerging periodontal pathogens evade and manipulate neutrophil functional mechanisms to initiate and maintain a cycle of inflammation that results in periodontitis. Here, we review the effect of established and emerging periodontal pathogens on each neutrophil function and link the aberrant neutrophil phenotype to the pathogenesis of periodontitis.
Filifactor alocis is a gram positive anaerobe that is emerging as an important periodontal pathogen. In the oral cavity F. alocis colonizes polymicrobial biofilm communities; however, little is known ...regarding the nature of the interactions between F. alocis and other oral biofilm bacteria. Here we investigate the community interactions of two strains of F. alocis with Streptococcus gordonii, Fusobacterium nucleatum, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, organisms with differing pathogenic potential in the oral cavity. In an in vitro community development model, S. gordonii was antagonistic to the accumulation of F. alocis into a dual species community. In contrast, F. nucleatum and the type strain of F. alocis formed a synergistic partnership. Accumulation of a low passage isolate of F. alocis was also enhanced by F. nucleatum. In three species communities of S. gordonii, F. nucleatum and F. alocis, the antagonistic effects of S. gordonii superseded the synergistic effects of F. nucleatum toward F. alocis. The interaction between A. actinomycetemcomitans and F. alocis was strain specific and A. actinomycetemcomitans could either stimulate F. alocis accumulation or have no effect depending on the strain. P. gingivalis and F. alocis formed heterotypic communities with the amount of P. gingivalis greater than in the absence of F. alocis. However, while P. gingivalis benefited from the relationship, levels of F. alocis in the dual species community were lower compared to F. alocis alone. The inhibitory effect of P. gingivalis toward F. alocis was dependent, at least partially, on the presence of the Mfa1 fimbrial subunit. In addition, AI-2 production by P. gingivalis helped maintain levels of F. alocis. Collectively, these results show that the pattern of F. alocis colonization will be dictated by the spatial composition of microbial microenvironments, and that the organism may preferentially accumulate at sites rich in F. nucleatum.
is a gram-negative facultative anaerobe and an opportunistic oral pathogen, strongly associated with periodontitis and other inflammatory diseases. Periodontitis is a chronic inflammation of the ...periodontium resulting from the inflammatory response of the host towards the dysbiotic microbial community present at the gingival crevice. Previously, our group identified catecholamines and iron as the signals that activate the QseBC two-component system in
, necessary for the organism to acquire iron as a nutrient to survive in the anaerobic environment. However, the source of catecholamines has not been identified. It has been reported that mouse neutrophils can release catecholamines. In periodontitis, large infiltration of neutrophils is found at the subgingival pocket; hence, we wanted to test the hypothesis that
exploits human neutrophils as a source for catecholamines. In the present study, we showed that human neutrophils synthesize, store, and release epinephrine, one of the three main types of catecholamines. Human neutrophil challenge with
induced exocytosis of neutrophil granule subtypes: secretory vesicles, specific granules, gelatinase granules, and azurophilic granules. In addition, by selectively inhibiting granule exocytosis, we present the first evidence that epinephrine is stored in azurophilic granules. Using QseC mutants, we showed that the periplasmic domain of the QseC sensor kinase is required for the interaction between
and epinephrine. Finally, epinephrine-containing supernatants collected from human neutrophils promoted
growth and induced the expression of the
operon under anaerobic conditions. Based on our findings, we propose that
promotes azurophilic granule exocytosis by neutrophils as an epinephrine source to promote bacterial survival.
Periodontitis is a chronic inflammatory infectious disease that affects the integrity of tooth‐supporting tissues and has adverse systemic consequences. Advances in sequencing technologies have ...uncovered organisms that are exclusively found in high numbers in periodontal lesions, such as the gram‐positive anaerobic rod, Filifactor alocis. F. alocis can manipulate neutrophil effector functions, which allows the organism to survive within these granulocytes. Several neutrophil functions have been tested in the context of F. alocis challenge, but the effect of the organism on neutrophil apoptosis is still unknown. RNA sequencing of human neutrophils challenged with F. alocis showed that apoptosis pathways were differentially regulated. Compared to media‐cultured controls, F. alocis‐challenged neutrophils maintain their nuclear morphology, do not stain for Annexin V or 7‐AAD, and have decreased DNA fragmentation. Inhibition of apoptosis by F. alocis involved reduced caspase‐3, −8, and − 9 activation and upregulation of important anti‐apoptotic proteins. Prolonged lifespan was dependent on contact through TLR2/6, and F. alocis‐challenged neutrophils retained their functional capacity to induce inflammation for longer timepoints. This is the first in‐depth characterization of neutrophil apoptotic programs in response to an oral pathogen and provides key information on how bacteria manipulate immune cell mechanisms to maintain a dysregulated inflammatory response.
Periodontitis is a chronic inflammatory infectious disease that results in tooth loss and increases the risk of other systemic diseases. The interaction between neutrophils and oral pathogens is a key determinant of disease progression. In this study, we characterize how an emerging oral pathogen, Filifactor alocis, prolongs neutrophil life span by modulation of apoptosis regulatory factors which allow neutrophils to retain their functional capacity to induce inflammation for prolong timepoints.
Summary Inflammation is a double-edged sword in the outcome of pneumonia. On the one hand, an effective and timely inflammatory response is required to eliminate the invading respiratory pathogen. On ...the other, a toxic and prolonged inflammatory response may result in lung injury and poor outcomes, even in those receiving advanced medical care. This review focuses on recent understanding of the dynamics of the cytokine response, neutrophil activity, and responsiveness to cytokines and neutrophil lifespan as major elements of lung inflammation resulting in favorable or poor outcomes in lung infection primarily due to pneumococcus and influenza virus. Although some progress has been made in our understanding of the molecular mechanisms of the pneumonia inflammation axis composed of cytokines modulating neutrophil activation and neutrophil apoptosis, important questions remain to be answered. The degree of neutrophil activation, generation of reactive oxygen species, and the release of granule antimicrobial peptides play a key role in microbial pathogen clearance; however, prolonged neutrophil activation may contribute to lung injury and poor outcomes in pneumonia. Molecular markers of the mechanisms regulating neutrophil survival and apoptosis may help in the identification of novel therapeutic targets to modulate inflammation by inducing timely neutrophil apoptosis. A major task is to identify the mechanisms of dysregulation in inflammation leading to toxic responses, thereby targeting a biomarker and enabling timely therapies to modulate inflammation.
Increased prevalence and abundance of Selenomonas sputigena have been associated with periodontitis, a chronic inflammatory disease of tooth-supporting tissues, for more than 50 years. Over the past ...decade, molecular surveys of periodontal disease using 16S and shotgun metagenomic sequencing approaches have confirmed the disease association of classically recognized periodontal pathogens such as Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia while highlighting previously underappreciated organisms such as Filifactor alocis and S. sputigena. Despite abundant clinical association between
and periodontal disease, we have little to no understanding of its pathogenic potential, and virulence mechanisms have not been studied. In this study, we sought to characterize the response of gingival epithelial cells to infection with
. Here, we show that
attaches to gingival keratinocytes and induces expression and secretion of cytokines and chemokines associated with inflammation and leukocyte recruitment. We demonstrate that
induces signaling through Toll-like receptor 2 (TLR2) and TLR4 but evades activation of TLR5. Cytokines released from
-infected keratinocytes induced monocyte and neutrophil chemotaxis. These results show that S.
-host interactions have the potential to contribute to bacterially driven inflammation and tissue destruction, the hallmark of periodontitis. Characterization of previously unstudied pathogens may provide novel approaches to develop therapeutics to treat or prevent periodontal disease.
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