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Glucocorticoids limit lipopolysaccharide-induced lethal inflammation by a double control system.

ABSTRACT: Lipopolysaccharides (LPS) can lead to a lethal endotoxemia, which is a systemic inflammatory response syndrome (SIRS) characterized by a systemic release of cytokines, such as TNF. Endotoxemia is studied intensely, as a model system of Gram-negative infections. LPS- and TNF-induced SIRS involve a strong induction of interferon-stimulated genes (ISGs), some of which cause cell death in the intestinal epithelium cells (IECs). It is well known that glucocorticoids (GCs) protect against endotoxemia. By applying numerous mutant mouse lines, our data support a model whereby GCs, via their glucocorticoid receptor (GR), apply two key mechanisms to control endotoxemia, (i) at the level of suppression of TNF production in a GR monomer-dependent way in macrophages and (ii) at the level of inhibition of TNFR1-induced ISG gene expression and necroptotic cell death mediators in IECs in a GR dimer-dependent way. Our data add new important insights to the understanding of the role of TNF in endotoxemia and the two separate key roles of GCs in suppressing TNF production and activity.

SUBMITTER: Van Looveren K

PROVIDER: S-EPMC7332980 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Glucocorticoids limit lipopolysaccharide-induced lethal inflammation by a double control system.

Van Looveren Kelly K Timmermans Steven S Vanderhaeghen Tineke T Wallaeys Charlotte C Ballegeer Marlies M Souffriau Jolien J Eggermont Melanie M Vandewalle Jolien J Van Wyngene Lise L De Bosscher Karolien K Libert Claude C

EMBO reports 20200508 7

Lipopolysaccharides (LPS) can lead to a lethal endotoxemia, which is a systemic inflammatory response syndrome (SIRS) characterized by a systemic release of cytokines, such as TNF. Endotoxemia is studied intensely, as a model system of Gram-negative infections. LPS- and TNF-induced SIRS involve a strong induction of interferon-stimulated genes (ISGs), some of which cause cell death in the intestinal epithelium cells (IECs). It is well known that glucocorticoids (GCs) protect against endotoxemia. ...[more]

PMID: 32383538

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Project description:Retinal neurodegenerative diseases involve a scenario of inflammation and cell death that leads to morphological alterations and visual impairment. Non-ocular inflammatory processes could affect neurodegenerative retinal disorders and their progression, at least in part by activating microglial cells and releasing pro-inflammatory cytokines. Our purpose was to study the consequences of a systemic inflammatory process in the progression of retinal degeneration in P23H rats, a retinitis pigmentosa (RP) model. In order to induce a mild chronic systemic inflammation, we administered low doses of lipopolysaccharide (LPS) from age P20 to P60 to dystrophic P23H rats and healthy SD rats. Visual responsiveness was assessed by electroretinography (ERG). The morphological state of the retinas was analyzed by fluorescent immunohistochemistry (IHC), evaluating the number, morphology, and connectivity of different neuronal populations by means of cell type-specific markers. Microglia density, distribution, and degree of activation were evaluated by IHC and flow cytometry. The expression levels of inflammation- and apoptosis-related genes were analyzed by qRT-PCR arrays. Low-dose LPS administration did not induce significant functional or morphological changes in the retina of SD rats, although at the molecular level, we detected expression changes in genes related to apoptosis. Otherwise, systemic injection of LPS into P23H rats induced a further deterioration in the ERG response, with greater loss of photoreceptors and worsening of synaptic connectivity, accompanied by increasing numbers of microglial cells, which also showed a more intense activation state. Several inflammation- and apoptosis-related genes were upregulated. Our results indicate that chronic exacerbation of the inflammatory response in response to LPS accelerates neurodegeneration in dystrophic P23H rats, suggesting that in patients with ocular neurodegenerative diseases, peripheral damage, as a systemic infection or chronic inflammatory process, could accelerate disease progression, and should be taken into account in order to select an appropriate therapy to revert, block or slow-down the degenerative process.

Project description:ObjectiveBacterial endotoxin (lipopolysaccharide)-mediated sepsis involves dysregulated systemic inflammation, which injures the lung and other organs, often fatally. Vascular endothelial cells act as both targets and mediators of lipopolysaccharide-induced inflammatory responses. Dysfunction of endothelium results in increases of proinflammatory cytokine production and permeability leakage. BMPER (bone morphogenetic protein-binding endothelial regulator), an extracellular modulator of bone morphogenetic protein signaling, has been identified as a vital component in chronic endothelial inflammatory responses and atherosclerosis. However, it is unclear whether BMPER also regulates inflammatory response in an acute setting such as sepsis. To address this question, we investigated the role of BMPER during lipopolysaccharide-induced acute lung injury.Approach and resultsMice missing 1 allele of BMPER (BMPER+/- mice used in the place of BMPER-/- mice that die at birth) were used for lipopolysaccharide challenge. Lipopolysaccharide-induced pulmonary inflammation and injury was reduced in BMPER+/- mice as shown by several measures, including survival rate, infiltration of inflammatory cells, edema, and production of proinflammatory cytokines. Mechanistically, we have demonstrated that BMPER is required and sufficient for the activation of nuclear factor of activated T cells c1. This BMPER-induced nuclear factor of activated T cells activation is coordinated by multiple signaling pathways, including bone morphogenetic protein-independent low-density lipoprotein receptor-related protein 1-extracellular signal-regulated kinase activation, calcineurin signaling, and low-density lipoprotein receptor-related protein 1β-mediated nuclear factor 45 nuclear export in response to BMPER treatment.ConclusionsWe conclude that BMPER plays a pivotal role in pulmonary inflammatory response, which provides new therapeutic options against sepsis shock. The new signaling pathway initiated by BMPER/low-density lipoprotein receptor-related protein 1 axis broadens our understanding about BMPER's role in vascular homeostasis.

Dataset Information

Glucocorticoids limit lipopolysaccharide-induced lethal inflammation by a double control system.

Publications

Glucocorticoids limit lipopolysaccharide-induced lethal inflammation by a double control system.

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