scholarly journals Neurosteroid allopregnanolone (3α,5α-THP) inhibits inflammatory signals induced by activated MyD88-dependent toll-like receptors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Irina Balan ◽  
Laure Aurelian ◽  
Riana Schleicher ◽  
Giorgia Boero ◽  
Todd O’Buckley ◽  
...  
Keyword(s):  
Rat Brain ◽  
Toll Like Receptor ◽  
Macrophage Cell ◽  
Toll Like Receptor 4 ◽  
Selective Agonist ◽  
Mouse Macrophages ◽  
Tlr3 Signaling ◽  
The Brain ◽  
Signal Activation ◽  
P Rat

AbstractWe have shown that endogenous neurosteroids, including pregnenolone and 3α,5α-THP inhibit toll-like receptor 4 (TLR4) signal activation in mouse macrophages and the brain of alcohol-preferring (P) rat, which exhibits innate TLR4 signal activation. The current studies were designed to examine whether other activated TLR signals are similarly inhibited by 3α,5α-THP. We report that 3α,5α-THP inhibits selective agonist-mediated activation of TLR2 and TLR7, but not TLR3 signaling in the RAW246.7 macrophage cell line. The TLR4 and TLR7 signals are innately activated in the amygdala and NAc from P rat brains and inhibited by 3α,5α-THP. The TLR2 and TLR3 signals are not activated in P rat brain and they are not affected by 3α,5α-THP. Co-immunoprecipitation studies indicate that 3α,5α-THP inhibits the binding of MyD88 with TLR4 or TLR7 in P rat brain, but the levels of TLR4 co-precipitating with TRIF are not altered by 3α,5α-THP treatment. Collectively, the data indicate that 3α,5α-THP inhibits MyD88- but not TRIF-dependent TLR signal activation and the production of pro-inflammatory mediators through its ability to block TLR-MyD88 binding. These results have applicability to many conditions involving pro-inflammatory TLR activation of cytokines, chemokines, and interferons and support the use of 3α,5α-THP as a therapeutic for inflammatory disease.

scholarly journals Toll-Like Receptor 4 (TLR4)-Deficient Murine Macrophage Cell Line as an In Vitro Assay System To Show TLR4-Independent Signaling of Bacteroides fragilis Lipopolysaccharide

2002 ◽  
Vol 70 (9) ◽  
pp. 4892-4896 ◽  
Author(s):  
Eva Lorenz ◽  
Dhavalkumar D. Patel ◽  
Thomas Hartung ◽  
David A. Schwartz
Keyword(s):  
Cell Line ◽  
Mouse Strain ◽  
Bacterial Species ◽  
Bacteroides Fragilis ◽  
Toll Like Receptor ◽  
Macrophage Cell Line ◽  
Macrophage Cell ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Vitro Assay

ABSTRACT Bacterial lipopolysaccharides (LPS) activate cells of innate immunity, such as macrophages, by stimulating signaling through toll-like receptor 4 (TLR4). We and others have hypothesized that LPS derived from different bacterial species may function through TLR4-independent mechanisms. To test this hypothesis, we have generated using a nonviral transformation procedure a bone marrow-derived macrophage cell line called 10ScNCr/23 from mouse strain C57BL/10ScNCr. This mouse strain has a deletion of the TLR4 locus, causing the mouse strain to be nonresponsive to stimulation by LPS from Escherichia coli while responding normally to other bacterial substrates, such as lipoteichoic acid (LTA) from Staphylococcus aureus, which signal TLR4 independently. Stimulation with LTA induces five- and sixfold increases in 10ScNCr/23 cell line tumor necrosis factor alpha and macrophage inflammatory protein-2 (MIP-2) secretion, but no increases in either cytokine were found when cells were stimulated with E. coli LPS. Bacteroides fragilis-derived LPS, however, can effectively stimulate MIP-2 expression in the absence of functional TLR4 in the 10ScNCr/23 cell line. This gives rise to the notion that LPS from some bacterial species will utilize alternative receptors to stimulate the innate immune response.

scholarly journals The Small GTPase Arf6 Is Essential for the Tram/Trif Pathway in TLR4 Signaling

2013 ◽  
Vol 289 (3) ◽  
pp. 1364-1376 ◽  
Author(s):  
Tim Van Acker ◽  
Sven Eyckerman ◽  
Lieselotte Vande Walle ◽  
Sarah Gerlo ◽  
Marc Goethals ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Critical Role ◽  
Adaptor Proteins ◽  
Small Gtpase ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Mouse Macrophages ◽  
Adp Ribosylation Factor ◽  
Irf3 Activation

Recognition of lipopolysaccharides (LPS) by Toll-like receptor 4 (TLR4) at the plasma membrane triggers NF-κB activation through recruitment of the adaptor proteins Mal and MyD88. Endocytosis of the activated TLR4 allows recruitment of the adaptors Tram and Trif, leading to activation of the transcription factor IRF3 and interferon production. The small GTPase ADP-ribosylation factor 6 (Arf6) was shown to regulate the plasma membrane association of Mal. Here we demonstrate that inhibition of Arf6 also markedly reduced LPS-induced cytokine production in Mal−/− mouse macrophages. In this article, we focus on a novel role for Arf6 in the MyD88-independent TLR4 pathway. MyD88-independent IRF3 activation and IRF3-dependent gene transcription were strictly dependent on Arf6. Arf6 was involved in transport of Tram to the endocytic recycling compartment and internalization of LPS, possibly explaining its requirement for LPS-induced IRF3 activation. Together, these results show a critical role for Arf6 in regulating Tram/Trif-dependent TLR4 signaling.

scholarly journals Lipid IVa incompletely activates MyD88-independent Toll-like receptor 4 signaling in mouse macrophage cell lines

2013 ◽  
Vol 67 (3) ◽  
pp. 199-205 ◽  
Author(s):  
Norihiko Ogura ◽  
Masashi Muroi ◽  
Yuka Sugiura ◽  
Ken-ichi Tanamoto
Keyword(s):  
Cell Lines ◽  
Mouse Macrophage ◽  
Toll Like Receptor ◽  
Macrophage Cell ◽  
Toll Like Receptor 4

scholarly journals Toll-like receptor-4 regulation of hepaticCyp3a11metabolism in a mouse model of LPS-induced CNS inflammation

2005 ◽  
Vol 289 (3) ◽  
pp. G434-G443 ◽  
Author(s):  
Kerry B. Goralski ◽  
Dalya Abdulla ◽  
Christopher J. Sinal ◽  
Andre Arsenault ◽  
Kenneth W. Renton
Keyword(s):  
Mouse Model ◽  
Cns Infection ◽  
Mouse Strains ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Cns Inflammation ◽  
Infection And Inflammation ◽  
Cytochrome P 450 ◽  
The Brain ◽  
Expression And Activity

Central nervous system (CNS) infection and inflammation severely reduce the capacity of cytochrome P-450 metabolism in the liver. We developed a mouse model to examine the effects of CNS inflammation on hepatic cytochrome P-450 metabolism. FVB, C57BL/6, and C3H/HeouJ mice were given Escherichia coli LPS (2.5 μg) by intracerebroventricular (ICV) injection. The CNS inflammatory response was confirmed by the elevation of TNF-α and/or IL-1β proteins in the brain. In all mouse strains, LPS produced a 60–70% loss in hepatic Cyp3a11 expression and activity compared with saline-injected controls. Adrenalectomy did not prevent the loss in Cyp3a11 expression or activity, thereby precluding the involvement of the hypothalamic-adrenal-pituitary axis. Endotoxin was detectable (1–10 ng/ml) in serum between 15 and 120 min after ICV dosing of 2.5 μg LPS. Peripheral administration of 2.5 μg LPS by intraperitoneal injection produced similar serum endotoxin levels and a similar loss (60%) in Cyp3a11 expression and activity in the liver. The loss of Cyp3a11 in response to centrally or peripherally administered LPS could not be evoked in Toll-like receptor-4 (TLR4)-mutant (C3H/HeJ) mice, indicating that TLR4 signaling pathways are directly involved in the enzyme loss. In summary, we conclude that LPS is transferred from the brain to the circulation in significant quantities in a model of CNS infection or inflammation. Subsequently, LPS that has reached the circulation stimulates a TLR4-dependent mechanism in the periphery, evoking a reduction in Cyp3a11 expression and metabolism in the liver.

Biological role of Toll-like receptor-4 in the brain

2014 ◽  
Vol 268 (1-2) ◽  
pp. 1-12 ◽  
Author(s):  
Teresa Trotta ◽  
Chiara Porro ◽  
Rosa Calvello ◽  
Maria Antonietta Panaro
Keyword(s):  
Biological Role ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
The Brain

scholarly journals Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Antonella Managò ◽  
Valentina Audrito ◽  
Francesca Mazzola ◽  
Leonardo Sorci ◽  
Federica Gaudino ◽  
...  
Keyword(s):  
Endotoxin Tolerance ◽  
Toll Like Receptor ◽  
Biosynthetic Activity ◽  
Toll Like Receptor 4 ◽  
Inflammatory Conditions ◽  
Mouse Macrophages ◽  
Macrophage Colony ◽  
Molecular Patterns

Abstract Damage-associated molecular patterns (DAMPs) are molecules that can be actively or passively released by injured tissues and that activate the immune system. Here we show that nicotinate phosphoribosyltransferase (NAPRT), detected by antibody-mediated assays and mass spectrometry, is an extracellular ligand for Toll-like receptor 4 (TLR4) and a critical mediator of inflammation, acting as a DAMP. Exposure of human and mouse macrophages to NAPRT activates the inflammasome and NF-κB for secretion of inflammatory cytokines. Furthermore, NAPRT enhances monocyte differentiation into macrophages by inducing macrophage colony-stimulating factor. These NAPRT-induced effects are independent of NAD-biosynthetic activity, but rely on NAPRT binding to TLR4. In line with our finding that NAPRT mediates endotoxin tolerance in vitro and in vivo, sera from patients with sepsis contain the highest levels of NAPRT, compared to patients with other chronic inflammatory conditions. Together, these data identify NAPRT as a endogenous ligand for TLR4 and a mediator of inflammation.

Sign in / Sign up

Export Citation Format

Share Document