Role of Toll-Like Receptor 4 in Intimal Foam Cell Accumulation in Apolipoprotein E–Deficient Mice

Background and Purpose— After stroke, the population of infiltrated neutrophils in the brain is heterogeneous, including a population of alternative neutrophils (N2) that express M2 phenotype markers. We explored the role of TLR4 (toll-like receptor 4) on neutrophil infiltration and polarization in this setting. Methods— Focal cerebral ischemia was induced by occlusion of the middle cerebral artery occlusion in TLR4-KO and WT (wild type) mice. Infarct size was measured by Nissl staining and magnetic resonance imaging. Leukocyte infiltration was quantified 48 hours after middle cerebral artery occlusion by immunofluorescence and flow cytometry. To elucidate mechanisms underlying TLR4-mediated N2 phenotype, a cDNA microarray analysis was performed in neutrophils isolated from blood 48 hours after stroke in WT and TLR4-KO mice. Results— As demonstrated previously, TLR4-deficient mice presented lesser infarct volumes than WT mice. TLR4-deficient mice showed higher density of infiltrated neutrophils 48 hours after stroke compared with WT mice, concomitantly to neuroprotection. Furthermore, cytometric and stereological analyses revealed an increased number of N2 neutrophils (YM1 + cells) into the ischemic core in TLR4-deficient mice, suggesting a protective effect of this neutrophil subset that was corroborated by depleting peripheral neutrophils or using mice with TLR4 genetically ablated in the myeloid lineage. Finally, cDNA microarray analysis in neutrophils, confirmed by quantitative polymerase chain reaction, showed that TLR4 modulates several pathways associated with ischemia-induced inflammation, migration of neutrophils into the parenchyma, and their functional priming, which might explain the opposite effect on outcome of the different neutrophil subsets. Conclusions— TLR4 deficiency increased the levels of alternative neutrophils (N2)—an effect associated with neuroprotection after stroke—supporting that modulation of neutrophil polarization is a major target of TLR4 and highlighting the crucial role of TLR4 at the peripheral level after stroke. Visual Overview— An online visual overview is available for this article.

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Pycnogenol Reduces Toll-Like Receptor 4 Signaling Pathway-Mediated Atherosclerosis Formation in Apolipoprotein E-Deficient Mice

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0000000000000415 ◽

2016 ◽

Vol 68 (4) ◽

pp. 292-303 ◽

Cited By ~ 3

Author(s):

Rui Liu ◽

Bin Fan ◽

Huiying Cong ◽

Shoichiro Ikuyama ◽

Haixia Guan ◽

...

Keyword(s):

Apolipoprotein E ◽

Signaling Pathway ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Deficient Mice

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Progress in Biochemistry and Biophysics》 2013-09Add to Favorite Get Latest Update Glycoprotein Ⅱb/Ⅲa mAb Decreases Atherosclerosis by Inhibiting High-Mobility Group Box-1/Toll-like Receptor 4 Signaling in Apolipoprotein-E-deficient Mice

ACTA AGRONOMICA SINICA ◽

10.3724/sp.j.1206.2012.00602 ◽

2013 ◽

Vol 40 (9) ◽

pp. 834

Author(s):

Hong-Feng GU ◽

Jian-Hong JIANG ◽

Duan-Fang LIAO ◽

Qiao-Zhen TONG ◽

Yong-Zong YANG

Keyword(s):

Apolipoprotein E ◽

High Mobility ◽

High Mobility Group ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Deficient Mice

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Activation of ASC Inflammasome Driven by Toll-Like Receptor 4 Contributes to Host Immunity against Rickettsial Infection

Infection and Immunity ◽

10.1128/iai.00886-19 ◽

2020 ◽

Vol 88 (4) ◽

Author(s):

Claire Rumfield ◽

Ilirjana Hyseni ◽

Jere W. McBride ◽

David H. Walker ◽

Rong Fang

Keyword(s):

Host Susceptibility ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Content Type ◽

Ifn Γ ◽

Human Infections ◽

Deficient Mice ◽

Dependent Mechanism

ABSTRACT Rickettsiae are cytosolically replicating, obligately intracellular bacteria causing human infections worldwide with potentially fatal outcomes. We previously showed that Rickettsia australis activates ASC inflammasome in macrophages. In the present study, host susceptibility of ASC inflammasome-deficient mice to R. australis was significantly greater than that of C57BL/6 (B6) controls and was accompanied by increased rickettsial loads in various organs. Impaired host control of R. australis in vivo in ASC−/− mice was associated with dramatically reduced levels of interleukin 1β (IL-1β), IL-18, and gamma interferon (IFN-γ) in sera. The intracellular concentrations of R. australis in bone marrow-derived macrophages (BMMs) of TLR4−/− and ASC−/− mice were significantly greater than those in BMMs of B6 controls, highlighting the important role of inflammasome and these molecules in controlling rickettsiae in macrophages. Compared to B6 BMMs, TLR4−/− BMMs failed to secrete a significant level of IL-1β and had reduced expression levels of pro-IL-1β in response to infection with R. australis, suggesting that rickettsiae activate ASC inflammasome via a Toll-like receptor 4 (TLR4)-dependent mechanism. Further mechanistic studies suggest that the lipopolysaccharide (LPS) purified from R. australis together with ATP stimulation led to cleavage of pro-caspase-1 and pro-IL-1β, resulting in TLR4-dependent secretion of IL-1β. Taken together, these observations indicate that activation of ASC inflammasome, most likely driven by interaction of TLR4 with rickettsial LPS, contributes to host protective immunity against R. australis. These findings provide key insights into defining the interactions of rickettsiae with the host innate immune system.

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Faculty Opinions recommendation of Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1283990.751098 ◽

2009 ◽

Author(s):

Matthias Ochs ◽

Christian Mühlfeld

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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Dihydrotanshinone I Attenuates Plaque Vulnerability in Apolipoprotein E-Deficient Mice: Role of Receptor-Interacting Protein 3

Antioxidants and Redox Signaling ◽

10.1089/ars.2019.7796 ◽

2020 ◽

Author(s):

Wenwen Zhao ◽

Chunxia Li ◽

Hao Zhang ◽

Qihui Zhou ◽

Xuehong Chen ◽

...

Keyword(s):

Apolipoprotein E ◽

Plaque Vulnerability ◽

Interacting Protein ◽

Deficient Mice

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Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

Anesthesiology ◽

10.1097/aln.0b013e3182608cc0 ◽

2012 ◽

Vol 117 (2) ◽

pp. 329-338 ◽

Cited By ~ 34

Author(s):

Willem-Jan M. Schellekens ◽

Hieronymus W. H. van Hees ◽

Michiel Vaneker ◽

Marianne Linkels ◽

P. N. Richard Dekhuijzen ◽

...

Keyword(s):

Mechanical Ventilation ◽

Caspase 3 ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Diaphragm Atrophy ◽

Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

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