scholarly journals Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhijuan Qiu ◽  
Jorge L. Cervantes ◽  
Basak B. Cicek ◽  
Subhajit Mukherjee ◽  
Madhukumar Venkatesh ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Bacterial Infection ◽  
Host Defense ◽  
Negative Impact ◽  
Pregnane X Receptor ◽  
Negative Regulator ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Chemokine Production ◽  
Inflammatory Monocytes

Abstract The nuclear pregnane X receptor (PXR) plays a central role in regulating xenobiotic metabolism. We now report a novel role for PXR as a critical negative regulator of innate immunity after infection. Pxr −/− mice exhibited remarkably elevated pro-inflammatory cytokine and chemokine production following infection with Listeria monocytogenes (Lm). Despite the more robust innate immune response, Pxr −/− mice were highly susceptible to Lm infection. Surprisingly, disruption of the Toll-like receptor 4 (TLR4) but not TLR2 signaling restored the inflammation to normal levels and the ability to clear Lm in Pxr −/− mice. Mechanistically, the heightened inflammation in Pxr −/− mice resulted in the death of inflammatory monocytes that led to the enhanced susceptibility to Lm infection. These data demonstrated that PXR regulated pathogen-induced inflammation and host defense against Lm infection through modulating the TLR4 pathway. In summary, we discovered an apical role for PXR in regulating innate immunity. In addition, we uncovered a remarkable negative impact of the TLR4 pathway in controlling the quality of the inflammatory response and host defense against a gram-positive bacterial infection.

scholarly journals Erratum: Corrigendum: Pregnane X Receptor Regulates Pathogen-Induced Inflammation and Host Defense against an Intracellular Bacterial Infection through Toll-like Receptor 4

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhijuan Qiu ◽  
Jorge L. Cervantes ◽  
Basak B. Cicek ◽  
Subhajit Mukherjee ◽  
Madhukumar Venkatesh ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Host Defense ◽  
Pregnane X Receptor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals The contribution of miR-122 to the innate immunity by regulating toll-like receptor 4 in hepatoma cells

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Liyu Shi ◽  
Xiaoqiu Zheng ◽  
Yuzhuo Fan ◽  
Xiaolan Yang ◽  
Aimei Li ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Hepatoma Cells ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Toll-like receptor 4 ablation in mdx mice reveals innate immunity as a therapeutic target in Duchenne muscular dystrophy

2014 ◽  
Vol 24 (8) ◽  
pp. 2147-2162 ◽  
Author(s):  
Christian Giordano ◽  
Kamalika Mojumdar ◽  
Feng Liang ◽  
Christian Lemaire ◽  
Tong Li ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Therapeutic Target ◽  
Mdx Mice ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

2017 ◽  
Vol 91 (6) ◽  
Author(s):  
Nicholas L. Cianciola ◽  
Stacey Chung ◽  
Danny Manor ◽  
Cathleen R. Carlin
Keyword(s):  
Innate Immunity ◽  
Endoplasmic Reticulum ◽  
Membrane Protein ◽  
Lipid Droplets ◽  
Cholesterol Transport ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Human Adenoviruses ◽  
Early Region ◽  
Early Region 3

ABSTRACT Human adenoviruses (Ads) generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, we wished to determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RIDα via its direct interaction with the sterol-binding protein ORP1L, a member of the evolutionarily conserved family of oxysterol-binding protein (OSBP)-related proteins (ORPs). Second, we wished to determine how this interaction regulates innate immunity to adenovirus. ORP1L is known to form highly dynamic contacts with endoplasmic reticulum-resident VAP proteins that regulate late endosome function under regulation of Rab7-GTP. Our studies have demonstrated that ORP1L-VAP complexes also support transport of LDL-derived cholesterol from endosomes to the endoplasmic reticulum, where it was converted to cholesteryl esters stored in lipid droplets when ORP1L was bound to RIDα. The virally induced mechanism counteracted defects in the predominant cholesterol transport pathway regulated by the late endosomal membrane protein Niemann-Pick disease type C protein 1 (NPC1) arising during early stages of viral infection. However, unlike NPC1, RIDα did not reconstitute transport to endoplasmic reticulum pools that regulate SREBP transcription factors. RIDα-induced lipid trafficking also attenuated proinflammatory signaling by Toll-like receptor 4, which has a central role in Ad pathogenesis and is known to be tightly regulated by cholesterol-rich “lipid rafts.” Collectively, these data show that RIDα utilizes ORP1L in a way that is distinct from its normal function in uninfected cells to fine-tune lipid raft cholesterol that regulates innate immunity to adenovirus in endosomes. IMPORTANCE Early region 3 proteins encoded by human adenoviruses that attenuate immune-mediated pathology have been a particularly rich source of information regarding intracellular protein trafficking. Our studies with the early region 3-encoded RIDα protein also provided fundamental new information regarding mechanisms of nonvesicular lipid transport and the flow of molecular information at membrane contacts between different organelles. We describe a new pathway that delivers cholesterol from endosomes to the endoplasmic reticulum, where it is esterified and stored in lipid droplets. Although lipid droplets are attracting renewed interest from the standpoint of normal physiology and human diseases, including those resulting from viral infections, experimental model systems for evaluating how and why they accumulate are still limited. Our studies also revealed an intriguing relationship between lipid droplets and innate immunity that may represent a new paradigm for viruses utilizing these organelles.

Toll-Like Receptor 4 in Rat Prostate: Modulation by Testosterone and Acute Bacterial Infection in Epithelial and Stromal Cells1

2006 ◽  
Vol 75 (5) ◽  
pp. 664-672 ◽  
Author(s):  
Amado A. Quintar ◽  
Felix D. Roth ◽  
Ana Lucía De Paul ◽  
Agustín Aoki ◽  
Cristina A. Maldonado
Keyword(s):  
Bacterial Infection ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Rat Prostate

scholarly journals Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease

2019 ◽  
Vol 216 (3) ◽  
pp. 482-500 ◽  
Author(s):  
Kyle Tretina ◽  
Eui-Soon Park ◽  
Agnieszka Maminska ◽  
John D. MacMicking
Keyword(s):  
Innate Immunity ◽  
Bacterial Infection ◽  
Host Defense ◽  
Tissue Damage ◽  
Binding Proteins ◽  
Wide Spectrum ◽  
Cell Types ◽  
Microbial Pathogens ◽  
Health And Disease ◽  
Basic Biology

Guanylate-binding proteins (GBPs) have recently emerged as central orchestrators of immunity to infection, inflammation, and neoplastic diseases. Within numerous host cell types, these IFN-induced GTPases assemble into large nanomachines that execute distinct host defense activities against a wide variety of microbial pathogens. In addition, GBPs customize inflammasome responses to bacterial infection and sepsis, where they act as critical rheostats to amplify innate immunity and regulate tissue damage. Similar functions are becoming evident for metabolic inflammatory syndromes and cancer, further underscoring the importance of GBPs within infectious as well as altered homeostatic settings. A better understanding of the basic biology of these IFN-induced GTPases could thus benefit clinical approaches to a wide spectrum of important human diseases.

scholarly journals Toll‐Like Receptor 4 Is Not Involved in Host Defense against PulmonaryLegionella pneumophilaInfection in a Mouse Model

2002 ◽  
Vol 186 (4) ◽  
pp. 570-573 ◽  
Author(s):  
Kamilla D. Lettinga ◽  
Sandrine Florquin ◽  
Peter Speelman ◽  
Ruud van Ketel ◽  
Tom van der Poll ◽  
...  
Keyword(s):  
Mouse Model ◽  
Host Defense ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals A Novel Role of Numb as A Regulator of Pro-inflammatory Cytokine Production in Macrophages in Response to Toll-like Receptor 4

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Patipark Kueanjinda ◽  
Sittiruk Roytrakul ◽  
Tanapat Palaga
Keyword(s):  
Notch Signaling ◽  
P38 Mapk ◽  
Inflammatory Responses ◽  
Notch Signaling Pathway ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Murine Bone Marrow

Abstract Activation of macrophages triggers the release of pro-inflammatory cytokines leading to inflammation. Numb is a negative regulator of Notch signaling, but the role of Numb in macrophages is not fully understood. In this study, the role of Numb as a regulator of inflammatory responses in macrophages was investigated. Murine bone marrow-derived macrophages, in which expression of Numb was silenced, secreted significantly less TNFα, IL-6 and IL-12 and more IL-10 upon activation by lipopolysaccharide (LPS), a ligand for Toll-like receptor 4 (TLR4), despite increased Notch signaling. The Tnfα mRNA levels both in Numb-deficient and wild-type macrophages were not significantly different, unlike those of Il6 and Il12-p40. In Numb-deficient macrophages, the Tnfα mRNAs were degraded at faster rate, compared to those in control macrophages. Activation of p38 MAPK and NF-κΒ p65 were compromised in activated Numb deficient macrophages. Numb was found to interact with the E3 ubiquitin ligase, Itch, which reportedly regulates p38 MAPK. In addition, blocking the Notch signaling pathway in activated, Numb-deficient macrophages did not further reduce TNFα levels, suggesting a Notch-independent role for Numb. A proteomics approach revealed a novel funciton for Numb in regulating complex signaling cascades downstream of TLRs, partially involving Akt/NF-κB p65/p38 MAPK in macrophages.

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