Abstract B097: Innate immune response to cell death in the post-partum mammary gland increases malignancy of parity-associated mammary tumors

Plants are constantly exposed to environmental biotic and abiotic stresses. Plants cells perceive these factors and trigger early responses followed by delayed and complex adaptation processes. Using cell suspensions of Arabidopsis thaliana (L.) as a cellular model, we investigated the role of plasma membrane anion channels in Reactive Oxygen Species (ROS) production and in cell death which occurs during non-host pathogen infection. Protoplasts derived from Arabidopsis suspension cells display two anion currents with characteristics very similar to those of the slow nitrate-permeable (S-type) and rapid sulfate-permeable (R-type) channels previously characterised in hypocotyl cells and other cell types. Using seven inhibitors, we showed that the R-type channel and ROS formation in cell cultures present similar pharmacological profiles. The efficiency of anion channel blockers to inhibit ROS production was independent of the nature of the triggering signal (osmotic stress or general elicitors of plant defence), indicating that the R-type channel represents a crossroad in the signalling pathways leading to ROS production. In a second step, we show that treatment with R-type channel blockers accelerates cell death triggered by the non-specific plant pathogen Xanthomonas campestris. Finally, we discuss the hypothesis that the R-type channel is involved in innate immune response allowing cell defence via antibacterial ROS production.

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Innate immune response of bovine mammary gland to pathogenic bacteria responsible for mastitis

Journal of Infection ◽

10.1016/j.jinf.2006.06.010 ◽

2007 ◽

Vol 54 (4) ◽

pp. 399-409 ◽

Cited By ~ 151

Author(s):

Javier Oviedo-Boyso ◽

Juan J. Valdez-Alarcón ◽

Marcos Cajero-Juárez ◽

Alejandra Ochoa-Zarzosa ◽

Joel E. López-Meza ◽

...

Keyword(s):

Immune Response ◽

Mammary Gland ◽

Innate Immune Response ◽

Pathogenic Bacteria ◽

Innate Immune ◽

Bovine Mammary Gland

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COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/6401341 ◽

2020 ◽

Vol 2020 ◽

pp. 1-34

Author(s):

Patrick C. Bradshaw ◽

William A. Seeds ◽

Alexandra C. Miller ◽

Vikrant R. Mahajan ◽

William M. Curtis

Keyword(s):

Immune Response ◽

Cell Death ◽

T Cell ◽

Energy Metabolism ◽

Respiratory Distress ◽

Ketogenic Diet ◽

Innate Immune Response ◽

Redox State ◽

Innate Immune ◽

Cytokine Storm

Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.

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Autophagy Negatively Regulates Cell Death by Controlling NPR1-Dependent Salicylic Acid Signaling during Senescence and the Innate Immune Response in Arabidopsis

The Plant Cell ◽

10.1105/tpc.109.068635 ◽

2009 ◽

Vol 21 (9) ◽

pp. 2914-2927 ◽

Cited By ~ 303

Author(s):

Kohki Yoshimoto ◽

Yusuke Jikumaru ◽

Yuji Kamiya ◽

Miyako Kusano ◽

Chiara Consonni ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

Salicylic Acid ◽

Innate Immune Response ◽

Innate Immune ◽

Salicylic Acid Signaling

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TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis.

10.1101/2021.06.12.448118 ◽

2021 ◽

Author(s):

Xiucui Ma ◽

David R Rawnsley ◽

Attila Kovacs ◽

Moydul Islam ◽

John T Murphy ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

Mitochondrial Dna ◽

Cardiac Myocytes ◽

Innate Immune Response ◽

Ischemia Reperfusion ◽

Adaptor Protein ◽

Mitochondrial Damage ◽

Innate Immune ◽

Rapid Decline

Mitochondrial damage triggers cell death signaling with catastrophic consequences in long-lived and irreplaceable cells, such as cardiac myocytes. Sensing of leaked mitochondrial DNA upon mitochondrial damage is also a potent trigger of inflammation. Whether the innate immune response pathways monitor mitochondrial damage in mitochondria-rich cardiac myocytes to prevent inflammation and cell death, remains unknown. TRAF2, an adaptor protein downstream of innate immune receptors, localizes to the mitochondria in the unstressed heart, with increased mitochondrial targeting in cardiomyopathic human hearts and after cardiac ischemia-reperfusion injury in mice. Inducible cardiomyocyte-specific deletion of TRAF2 in young adult mice impairs mitophagy with rapid decline in mitochondrial quality, upregulates TLR9 expression in cardiac myocytes, and results in inflammation and cell death manifesting as a fulminant cardiomyopathy. Preventing TLR9-mediated mitochondrial DNA sensing and resultant inflammation provides a short-term reprieve from cardiomyopathy, but persistence of damaged mitochondria results in long-term recrudescence. Restoration of TRAF2, but not the E3 ubiquitin ligase deficient mutant improves mitochondrial quality and rescues cardiomyopathy to restore homeostasis. Thus, the innate immune response acts via TRAF2 as the first line of defense against mitochondrial damage by orchestrating homeostatic mitophagy to dampen myocardial inflammation and prevent cell death.

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Assessment of epithelial cells' immune and inflammatory response to Staphylococcus aureus when exposed to a macrolide

Journal of Dairy Research ◽

10.1017/s0022029910000531 ◽

2010 ◽

Vol 77 (4) ◽

pp. 404-410 ◽

Cited By ~ 9

Author(s):

Maria Mazzilli ◽

Alfonso Zecconi

Keyword(s):

Staphylococcus Aureus ◽

Immune Response ◽

Mammary Gland ◽

Epithelial Cells ◽

Inflammatory Response ◽

Innate Immune Response ◽

Innate Immune ◽

Positive Interactions ◽

Staph Aureus ◽

Immune Defences

Non-specific (innate) immune response plays a major role in defending the udder from bacterial invasion. Moreover, recent investigations suggest that mammary gland epithelial cells (MGEC) could have a large and important role as a source of soluble components of immune defences. Despite many attempts to find other ways to control/prevent mastitis (i.e. vaccine) antimicrobial therapy is still the most used and effective means of curing clinical and subclinical mastitis. However, drug concentrations and therapy durations are far from the optimal in order to reduce costs. Therefore, efficacy of antimicrobial therapy is dependent not only on the substance activity but also on the positive interactions with the host innate immune response. Surprisingly, information on these interactions is rather scarce in the mastitis field. A simple experimental model was developed based on BME-UV cell line, Staphylococcus aureus as a challenge and a macrolide as an antimicrobial to assess the interactions among epithelial cells, Staph. aureus and the potential effects of antimicrobials on the immune system. The results of this study confirmed that tylosin has good antimicrobial activity against both intracellular and extracellular Staph. aureus in bovine MGEC without affecting cell functions. In this study, a significant down-regulation of IL-1 and IL-6 was observed, while TNF and IL-8 expression rate numerically increased, but differences were not significant. To our knowledge, this is the first paper assessing the concentration of two lysosomal enzymes, lysozyme and N-acetyl-β-d-glucosaminidase (NAGase), in Staph. aureus-stimulated MGEC. The results of this study confirmed that tylosin could have a significant effect on the release of these enzymes. Moreover, even if both enzymes have a similar substrate as a target, the results suggest different secretion mechanisms and an influence of antimicrobial treatment on these mechanisms. Successful mastitis cure is the result of achieving the optimal efficiency of both innate immune defences and therapeutical activities, by means of killing bacteria without eliciting an excessive inflammatory response. Therefore, antimicrobials for mastitis therapy should be selected not only on bacterial sensitivity, but also for their positive interactions with the innate immune response of the mammary gland. This study showed that an in-vitro model based on Staph. aureus challenge on MGEC could be helpful in assessing both the intracellular and extracellular activity of antimicrobials and their influence on epithelial cell immune and inflammatory response.

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