Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum) are Gram-negative anaerobic bacteria possessing several virulence factors that make them potential pathogens ...associated with periodontal disease. Periodontal diseases are chronic inflammatory diseases of the oral cavity, including gingivitis and periodontitis. Periodontitis can lead to tooth loss and is considered one of the most prevalent diseases worldwide. P. gingivalis and F. nucleatum possess virulence factors that allow them to survive in hostile environments by selectively modulating the host’s immune-inflammatory response, thereby creating major challenges to host cell survival. Studies have demonstrated that bacterial infection and the host immune responses are involved in the induction of periodontitis. The NLRP3 inflammasome and its effector molecules (IL-1β and caspase-1) play roles in the development of periodontitis. We and others have reported that the purinergic P2X7 receptor plays a role in the modulation of periodontal disease and intracellular pathogen control. Caspase-4/5 (in humans) and caspase-11 (in mice) are important effectors for combating bacterial pathogens via mediation of cell death and IL-1β release. The exact molecular events of the host’s response to these bacteria are not fully understood. Here, we review innate and adaptive immune responses induced by P. gingivalis and F. nucleatum infections and discuss the possibility of manipulations of the immune response as therapeutic strategies. Given the global burden of periodontitis, it is important to develop therapeutic targets for the prophylaxis of periodontopathogen infections.
A growing body of literature suggests that there is a link between periodontitis and systemic diseases. These diseases include cardiovascular disease, gastrointestinal and colorectal cancer, diabetes ...and insulin resistance, and Alzheimer's disease, as well as respiratory tract infection and adverse pregnancy outcomes. The presence of periodontal pathogens and their metabolic by-products in the mouth may in fact modulate the immune response beyond the oral cavity, thus promoting the development of systemic conditions. A cause-and-effect relationship has not been established yet for most of the diseases, and the mediators of the association are still being identified. A better understanding of the systemic effects of oral microorganisms will contribute to the goal of using the oral cavity to diagnose and possibly treat non-oral systemic disease.
The role of NOD-like receptors in innate immunity Almeida-da-Silva, Cássio Luiz Coutinho; Savio, Luiz Eduardo Baggio; Coutinho-Silva, Robson ...
Frontiers in immunology,
03/2023, Letnik:
14
Journal Article
Recenzirano
Odprti dostop
The innate immune system in vertebrates and invertebrates relies on conserved receptors and ligands, and pathways that can rapidly initiate the host response against microbial infection and other ...sources of stress and danger. Research into the family of NOD-like receptors (NLRs) has blossomed over the past two decades, with much being learned about the ligands and conditions that stimulate the NLRs and the outcomes of NLR activation in cells and animals. The NLRs play key roles in diverse functions, ranging from transcription of MHC molecules to initiation of inflammation. Some NLRs are activated directly by their ligands, while other ligands may have indirect effects on the NLRs. New findings in coming years will undoubtedly shed more light on molecular details involved in NLR activation, as well as the physiological and immunological outcomes of NLR ligation.
Boswellia trees, found throughout the Middle East and parts of Africa and Asia, are the source of frankincense oil. Since antiquity, frankincense has been traded as a precious commodity, but it has ...also been used for the treatment of chronic disease, inflammation, oral health, and microbial infection. More recently, the bioactive components of Boswellia trees have been identified and characterized for their effects on cancer, microbial infection (especially infection by oral pathogens), and inflammation. Most studies have focused on cell lines, but more recent research has also investigated effects in animal models of disease. As natural products are considered to be safer than synthetic drugs, there is growing interest in further developing the use of substances such as frankincense oil for therapeutic treatment.
A large body of evidence shows the harmful effects of cigarette smoke to oral and systemic health. More recently, a link between smoking and susceptibility to coronavirus disease 2019 (COVID-19) was ...proposed. COVID-19 is due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which uses the receptor ACE2 and the protease TMPRSS2 for entry into host cells, thereby infecting cells of the respiratory tract and the oral cavity. Here, we examined the effects of cigarette smoke on the expression of SARS-CoV-2 receptors and infection in human gingival epithelial cells (GECs). We found that cigarette smoke condensates (CSC) upregulated ACE2 and TMPRSS2 expression in GECs, and that CSC activated aryl hydrocarbon receptor (AhR) signaling in the oral cells. ACE2 was known to mediate SARS-CoV-2 internalization, and we demonstrate that CSC treatment potentiated the internalization of SARS-CoV-2 pseudovirus in GECs in an AhR-dependent manner. AhR depletion using small interference RNA decreased SARS-CoV-2 pseudovirus internalization in CSC-treated GECs compared with control GECs. Our study reveals that cigarette smoke upregulates SARS-CoV-2 receptor expression and infection in oral cells. Understanding the mechanisms involved in SARS-CoV-2 infection in cells of the oral cavity may suggest therapeutic interventions for preventing viral infection and transmission.
is the protozoan parasite that causes toxoplasmosis, a potentially fatal disease to immunocompromised patients, and which affects approximately 30% of the world's population. Previously, we showed ...that purinergic signaling
the P2X7 receptor contributes to
elimination in macrophages, through reactive oxygen species (ROS) production and lysosome fusion with the parasitophorous vacuole. Moreover, we demonstrated that P2X7 receptor activation promotes the production of anti-parasitic pro-inflammatory cytokines during early
infection
. However, the cascade of signaling events that leads to parasite elimination
P2X7 receptor activation remained to be elucidated. Here, we investigated the cellular pathways involved in
elimination triggered by P2X7 receptor signaling, during early infection in macrophages. We focused on the potential role of the inflammasome, a protein complex that can be co-activated by the P2X7 receptor, and which is involved in the host immune defense against
infection. Using peritoneal and bone marrow-derived macrophages from knockout mice deficient for inflammasome components (NLRP3
, Caspase-1/11
, Caspase-11
), we show that the control of
infection
P2X7 receptor activation by extracellular ATP (eATP) depends on the canonical inflammasome effector caspase-1, but not on caspase-11 (a non-canonical inflammasome effector). Parasite elimination
P2X7 receptor and inflammasome activation was also dependent on ROS generation and pannexin-1 channel. Treatment with eATP increased IL-1β secretion from infected macrophages, and this effect was dependent on the canonical NLRP3 inflammasome. Finally, treatment with recombinant IL-1β promoted parasite elimination
mitochondrial ROS generation (as assessed using Mito-TEMPO). Together, our results support a model where P2X7 receptor activation by eATP inhibits
growth in macrophages by triggering NADPH-oxidase-dependent ROS production, and also by activating a canonical NLRP3 inflammasome, which increases IL-1β production (
caspase-1 activity), leading to mitochondrial ROS generation.
Extracellular nucleotides are important mediators of activation, triggering various responses through plasma membrane P2 and P1 receptors. P2 receptors are further subdivided into ionotropic P2X ...receptors and G protein-coupled P2Y receptors. P2X4 is an ATP-gated cation channel broadly expressed in most tissues of the body. Within the P2X family, P2X4 has a unique subcellular distribution, being preferentially localized in lysosomes. In these organelles, high ATP concentrations do not trigger P2X4 because of the low pH. However, when the pH increases to 7.4, P2X4 can be stimulated by intra-lysosomal ATP, which is in its active, tetra-anionic form. Elucidation of P2X4, P2X3 and P2X7 structures has shed some light on the functional differences between these purinergic receptors. The potential interaction between P2X4 and P2X7 has been extensively studied. Despite intensive effort, it has not been possible yet to determine whether P2X4 and P2X7 interact as heterotrimers or homotrimers at the plasma membrane. However, several publications have shown that functional interactions between P2X4 and P2X7 do occur. Importantly, these studies indicate that P2X4 potentiates P2X7-dependent activation of inflammasomes, leading to increased release of IL-1β and IL-18. The role of P2X4 in various diseases could be beneficial or deleterious even though the pathophysiological mechanisms involved are still poorly defined. However, in diseases whose physiopathology involves activation of the NLRP3 inflammasome, P2X4 was found to exacerbate severity of disease. The recent production of monoclonal antibodies specific for the human and mouse P2X4, some of which are endowed with agonist or antagonist properties, raises the possibility that they could be used therapeutically. Analysis of single nucleotide polymorphisms of the human
gene has uncovered the association of
gene variants with susceptibility to several human diseases.
Conventional cigarette smoke harms nearly every organ of the body and is the leading cause of death in the United States and in the world. Decades of research have associated conventional cigarette ...smoke with several diseases and death. Heavily marketed, electronic nicotine delivery systems such as electronic cigarettes (e-cigarettes) are available in a variety of flavors and high nicotine concentrations. In 2019, a severe lung disease outbreak linked to e-cigarette use led to several deaths, which was called electronic-cigarette or vaping product use-associated lung injury (EVALI). Even though the trend of e-cigarette use among teens continues to increase, information on the effects of e-cigarette smoke on oral and overall health are still scarce. This review discusses the possible health effects due to unregulated e-cigarette use, as well as the health effects of second-hand smoke and third-hand smoke on non-smokers.
Frankincense is produced by
trees, which can be found throughout the Middle East and parts of Africa and Asia.
extract has been shown to have anti-cancer, anti-inflammatory, and antimicrobial ...effects. Periodontitis is an oral chronic inflammatory disease that affects nearly half of the US population. We investigated the antimicrobial effects of
extract on two oral pathogens associated with periodontitis. Using the minimum inhibitory concentration and crystal violet staining methods, we demonstrated that
growth and biofilm formation were impaired by treatment with
extracts. However, the effects on
growth and biofilm formation were not significant. Using quantification of colony-forming units and microscopy techniques, we also showed that concentrations of
that were not toxic for host cells decreased intracellular
infection in human gingival epithelial cells. Our results show antimicrobial activity of a natural product extracted from
trees (
) against periodontopathogens. Thus,
has the potential for preventing and/or treating periodontal diseases. Future studies will identify the molecular components of
extracts responsible for the beneficial effects.
•The canonical P2 × 7-Caspase-1 pathway is necessary for secretion of IL-1β in oral tissues and macrophages infected with P. gingivalis.•P2 × 7 receptor controls bacterial load of F. nucleatum and P. ...gingivalis in macrophages and in mice.•Caspase-11 is essential for F. nucleatum-induced secretion of IL-1β in macrophages, limits F. nucleatum infection in macrophages and in mice, and is required for cell death induced by F. nucleatum infection.•The canonical inflammasome is activated preferentially in response to P. gingivalis infection, while the noncanonical inflammasome plays a predominant role during F. nucleatum infection.
We examined the involvement of the P2 × 7 receptor and the canonical and noncanonical inflammasomes in the control of single-species or dual-species infection by the periodontal bacteria Porphyromonas gingivalis and Fusobacterium nucleatum in cells and mice. Stimulation of the P2 × 7 receptor leads to activation of the canonical NLRP3 inflammasome and activation of caspase-1, which leads to cleavage of pro-IL-1β to IL-1β, a key cytokine in the host inflammatory response in periodontal disease. The non-canonical inflammasome pathway involves caspase-11. Thus, wildtype (WT), P2 × 7−/−, caspase-11−/− and caspase-1/11−/− mice were co-infected with both bacterial species. In parallel, bone marrow-derived macrophages (BMDMs) from WT mice and the different knockout mice were infected with P. gingivalis and/or F. nucleatum, and treated or not with extracellular ATP, which is recognized by P2 × 7. F. nucleatum infection alone promoted secretion of IL-1β in BMDMs. Conversely, the canonical pathway involving P2 × 7 and caspase-1 was necessary for secretion of IL-1β in BMDMs infected with P. gingivalis and in the mandible of mice coinfected with P. gingivalis and F. nucleatum. The P2 × 7 pathway can limit bacterial load in single-species and dual-species infection with P. gingivalis and F. nucleatum in BMDMs and in mice. The non-canonical pathway involving caspase-11 was required for secretion of IL-1β induced by F. nucleatum infection in BMDMs, without treatment with ATP. Caspase-11 was also required for induction of cell death during infection with F. nucleatum and contributed to limiting bacterial load during F. nucleatum infection in BMDMs and in the gingival tissue of mice coinfected with P. gingivalis and F. nucleatum. Together, these data suggest that the P2 × 7-caspase-1 and caspase-11 pathways are involved in the immune response against infection by P. gingivalis and F. nucleatum, respectively.
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