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Neutrophil Extracellular Traps in Periodontitis.
Magán-Fernández, A, Rasheed Al-Bakri, SM, O'Valle, F, Benavides-Reyes, C, Abadía-Molina, F, Mesa, F
Cells. 2020;(6)
Abstract
Neutrophils are key cells of the immune system and have a decisive role in fighting foreign pathogens in infectious diseases. Neutrophil extracellular traps (NETs) consist of a mesh of DNA enclosing antimicrobial peptides and histones that are released into extracellular space following neutrophil response to a wide range of stimuli, such as pathogens, host-derived mediators and drugs. Neutrophils can remain functional after NET formation and are important for periodontal homeostasis. Periodontitis is an inflammatory multifactorial disease caused by a dysbiosis state between the gingival microbiome and the immune response of the host. The pathogenesis of periodontitis includes an immune-inflammatory component in which impaired NET formation and/or elimination can be involved, contributing to an exacerbated inflammatory reaction and to the destruction of gingival tissue. In this review, we summarize the current knowledge about the role of NETs in the pathogenesis of periodontitis.
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EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation.
Gilardini Montani, MS, Santarelli, R, Granato, M, Gonnella, R, Torrisi, MR, Faggioni, A, Cirone, M
Autophagy. 2019;(4):652-667
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Abstract
EBV has been reported to impair monocyte in vitro differentiation into dendritic cells (DCs) and reduce cell survival. In this study, we added another layer of knowledge to this topic and showed that these effects correlated with macroautophagy/autophagy, ROS and mitochondrial biogenesis reduction. Of note, autophagy and ROS, although strongly interconnected, have been separately reported to be induced by CSF2/GM-CSF (colony stimulating factor 2) and required for CSF2-IL4-driven monocyte in vitro differentiation into DCs. We show that EBV infects monocytes and initiates a feedback loop in which, by inhibiting autophagy, reduces ROS and through ROS reduction negatively influences autophagy. Mechanistically, autophagy reduction correlated with the downregulation of RAB7 and ATG5 expression and STAT3 activation, leading to the accumulation of SQSTM1/p62. The latter activated the SQSTM1-KEAP1- NFE2L2 axis and upregulated the anti-oxidant response, reducing ROS and further inhibiting autophagy. ROS decrease correlated also with the reduction of mitochondria, the main source of intracellular ROS, achieved by the downregulation of NRF1 and TFAM, mitochondrial biogenesis transcription factors. Interestingly, mitochondria supply membranes and ATP required for autophagy execution, thus their reduction may further reduce autophagy in EBV-infected monocytes. In conclusion, this study shows for the first time that the interconnected reduction of autophagy, intracellular ROS and mitochondria mediated by EBV switches monocyte differentiation into apoptosis, giving new insights into the mechanisms through which this virus reduces immune surveillance. Abbreviations: ACTB actin beta; ATG5: autophagy related 5; BAF: bafilomycin A1; BECN1: beclin 1; CAT: catalase; CSF2: colony stimulating factor 2; CT: control; CYCS (cytochrome C: somatic); DCs: dendritic cells; EBV: Epstein-Barr virus; GSR: glutathione-disulfide reductase; KEAP1: kelch like ECH associated protein 1; IL4: interleukin 4; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MET: metformin; NAC: N-acetylcysteine; NFE2L2/NRF2 nuclear factor: erythroid 2 like 2; NRF1 (nuclear respiratory factor 1); clPARP1: cleaved poly(ADP-ribose) polymerase; Rapa: Rapamycin; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TFAM (transcription factor A: mitochondrial); TUBA1A: tubulin alpha 1a.
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A thermodynamically-constrained mathematical model for the kinetics and regulation of NADPH oxidase 2 complex-mediated electron transfer and superoxide production.
Tomar, N, Sadri, S, Cowley, AW, Yang, C, Quryshi, N, Pannala, VR, Audi, SH, Dash, RK
Free radical biology & medicine. 2019;:581-597
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Abstract
Reactive oxygen species (ROS) play an important role in cell signaling, growth, and immunity. However, when produced in excess, they are toxic to the cell and lead to premature aging and a myriad of pathologies, including cardiovascular and renal diseases. A major source of ROS in many cells is the family of NADPH oxidase (NOX), comprising of membrane and cytosolic components. NOX2 is among the most widely expressed and well-studied NOX isoform. Although details on the NOX2 structure, its assembly and activation, and ROS production are well elucidated experimentally, there is a lack of a quantitative and integrative understanding of the kinetics of NOX2 complex, and the various factors such as pH, inhibitory drugs, and temperature that regulate the activity of this oxidase. To this end, we have developed here a thermodynamically-constrained mathematical model for the kinetics and regulation of NOX2 complex based on diverse published experimental data on the NOX2 complex function in cell-free and cell-based assay systems. The model incorporates (i) thermodynamics of electron transfer from NADPH to O2 through different redox centers of the NOX2 complex, (ii) dependence of the NOX2 complex activity upon pH and temperature variations, and (iii) distinct inhibitory effects of different drugs on the NOX2 complex activity. The model provides the first quantitative and integrated understanding of the kinetics and regulation of NOX2 complex, enabling simulation of diverse experimental data. The model also provides several novel insights into the NOX2 complex function, including alkaline pH-dependent inhibition of the NOX2 complex activity by its reaction product NADP+. The model provides a mechanistic framework for investigating the critical role of NOX2 complex in ROS production and its regulation of diverse cellular functions in health and disease. Specifically, the model enables examining the effects of specific targeting of various enzymatic sources of pathological ROS which could overcome the limitations of pharmacological efforts aimed at scavenging ROS which has resulted in poor outcomes of antioxidant therapies in clinical studies.
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NPR1 and Redox Rhythmx: Connections, between Circadian Clock and Plant Immunity.
Zhang, J, Ren, Z, Zhou, Y, Ma, Z, Ma, Y, Hou, D, Xu, Z, Huang, X
International journal of molecular sciences. 2019;(5)
Abstract
The circadian clock in plants synchronizes biological processes that display cyclic 24-h oscillation based on metabolic and physiological reactions. This clock is a precise timekeeping system, that helps anticipate diurnal changes; e.g., expression levels of clock-related genes move in synchrony with changes in pathogen infection and help prepare appropriate defense responses in advance. Salicylic acid (SA) is a plant hormone and immune signal involved in systemic acquired resistance (SAR)-mediated defense responses. SA signaling induces cellular redox changes, and degradation and rhythmic nuclear translocation of the non-expresser of PR genes 1 (NPR1) protein. Recent studies demonstrate the ability of the circadian clock to predict various potential attackers, and of redox signaling to determine appropriate defense against pathogen infection. Interaction of the circadian clock with redox rhythm promotes the balance between immunity and growth. We review here a variety of recent evidence for the intricate relationship between circadian clock and plant immune response, with a focus on the roles of redox rhythm and NPR1 in the circadian clock and plant immunity.
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Plasmodesmal regulation during plant-pathogen interactions.
Cheval, C, Faulkner, C
The New phytologist. 2018;(1):62-67
Abstract
Contents Summary 62 I. Introduction 62 II. Plasmodesmal regulation is an innate defence response 63 III. Reactive oxygen species regulate plasmodesmal function 63 IV. Plasmodesmal regulation by and of defence-associated small molecules 64 V. Plasmodesmata facilitate systemic defence signalling 64 VI. Virulent pathogens exploit plasmodesmata 66 VII. Outlook 66 Acknowledgements 66 References 66 SUMMARY Plasmodesmata (PD) are plasma membrane-lined pores that connect neighbouring plant cells, bridging the cell wall and establishing cytoplasmic and membrane continuity between cells. PD are dynamic structures regulated by callose deposition in a variety of stress and developmental contexts. This process crudely controls the aperture of the pore and thus the flux of molecules between cells. During pathogen infection, plant cells initiate a range of immune responses and it was recently identified that, following perception of fungal and bacterial pathogens, plant cells initially close their PD. Systemic defence responses depend on the spread of signals between cells, raising questions about whether PD are in different functional states during different immune responses. It is well established that viral pathogens exploit PD to spread between cells, but it has more recently been identified that protein effectors secreted by fungal pathogens can spread between host cells via PD. It is possible that many classes of pathogens specifically target PD to aid infection, which would infer antagonistic regulation of PD by host and pathogen. How PD regulation benefits both host immune responses and pathogen infection is an important question and demands that we examine the multicellular nature of plant-pathogen interactions.