Dataset Information

Polarization of Low-Grade Inflammatory Monocytes Through TRAM-Mediated Up-Regulation of Keap1 by Super-Low Dose Endotoxin.

ABSTRACT: Subclinical endotoxemia [low levels of bacterial endotoxin (LPS) in the blood stream] has been correlated with chronic inflammatory diseases, with less-understood mechanisms. We have previously shown that chronic exposure to super low doses of LPS polarizes monocytes/macrophages to a pro-inflammatory state characterized by up-regulation of pro-inflammatory regulators such as p62 and simultaneous down-regulation of anti-inflammatory/resolving regulators such as Nrf2. Building upon this observation, here we show that chronic exposure to super-low doses of LPS leads to accumulation of the Nrf2-inhibitory protein Keap1 in murine monocytes. This is accompanied by increases of p62 and MLKL, consistent with a disruption of autolysosome function in polarized monocytes challenged by super-low dose LPS. Monocytes subjected to persistent super-low dose LPS challenge also accumulate higher levels of IKK?. As a consequence, SLD-LPS challenge leads to an inflammatory monocyte state represented by higher expression of the inflammatory marker Ly6C as well as lower expression of the anti-inflammatory marker CD200R. Further analysis revealed that Keap1 levels are significantly enriched in the Ly6Chi pro-inflammatory monocyte population. Finally, we show that the TLR4 signaling adaptor TRAM is essential for these effects. Together our study provides novel insight into signaling mechanisms behind low-grade inflammatory monocyte polarization unique to chronic super-low dose LPS exposure.

SUBMITTER: Rahtes A

PROVIDER: S-EPMC7378438 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Polarization of Low-Grade Inflammatory Monocytes Through TRAM-Mediated Up-Regulation of Keap1 by Super-Low Dose Endotoxin.

Rahtes Allison A Li Liwu L

Frontiers in immunology 20200716

Subclinical endotoxemia [low levels of bacterial endotoxin (LPS) in the blood stream] has been correlated with chronic inflammatory diseases, with less-understood mechanisms. We have previously shown that chronic exposure to super low doses of LPS polarizes monocytes/macrophages to a pro-inflammatory state characterized by up-regulation of pro-inflammatory regulators such as p62 and simultaneous down-regulation of anti-inflammatory/resolving regulators such as Nrf2. Building upon this observatio ...[more]

PMID: 32765513

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Project description:Neutrophils are the first responders to infection and play a pivotal role in many inflammatory diseases, including sepsis. Recent studies have shown that lipopolysaccharide (LPS), a classical pattern recognition molecule, dynamically programs innate immune responses. In this study, we show that pre-treatment with super-low levels of LPS [1 ng/mL] significantly dysregulate neutrophil migratory phenotypes, including spontaneous migration and altering neutrophil decision-making. To quantify neutrophil migratory decision-making with single-cell resolution, we developed a novel microfluidic competitive chemotaxis-chip (μC3) that exposes cells in a central channel to competing chemoattractant gradients. In this reductionist approach, we use two chemoattractants: a pro-resolution (N-Formyl-Met-Leu-Phe, fMLP) and pro-inflammatory (Leukotriene B4, LTB4) chemoattractant to model how a neutrophil makes a decision to move toward an end target chemoattractant (e.g., bacterial infection) vs. an intermediary chemoattractant (e.g., inflammatory signal). We demonstrate that naïve neutrophils migrate toward the primary end target signal in higher percentages than toward the secondary intermediary signal. As expected, we found that training with high dose LPS [100 ng/mL] influences a higher percentage of neutrophils to migrate toward the end target signal, while reducing the percentage of neutrophils that migrate toward the intermediary signal. Surprisingly, super-low dose LPS [1 ng/mL] significantly changes the ratios of migrating cells and an increased percentage of cells migrate toward the intermediary signal. Significantly, there was also an increase in the numbers of spontaneously migrating neutrophils after treatment with super-low dose LPS. These results shed light onto the directional migratory decision-making of neutrophils exposed to inflammatory training signals. Understanding these mechanisms may lead to the development of pro-resolution therapies that correct the neutrophil compass and reduce off-target organ damage.

Dataset Information

Polarization of Low-Grade Inflammatory Monocytes Through TRAM-Mediated Up-Regulation of Keap1 by Super-Low Dose Endotoxin.

Publications

Polarization of Low-Grade Inflammatory Monocytes Through TRAM-Mediated Up-Regulation of Keap1 by Super-Low Dose Endotoxin.

Similar Datasets

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