scholarly journals In Vivo Expression of Proinflammatory Mediators in the Adult Heart after Endotoxin Administration: The Role of Toll‐Like Receptor–4

2001 ◽  
Vol 183 (11) ◽  
pp. 1617-1624 ◽  
Author(s):  
Georg Baumgarten ◽  
Pascal Knuefermann ◽  
Naoki Nozaki ◽  
Natarajan Sivasubramanian ◽  
Douglas L. Mann ◽  
...  
Keyword(s):  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Adult Heart ◽  
Endotoxin Administration ◽  
Proinflammatory Mediators ◽  
In Vivo Expression

scholarly journals In Vivo Evidence for a Role of Toll-Like Receptor 4 in the Development of Intimal Lesions

Circulation ◽  
2002 ◽  
Vol 106 (15) ◽  
pp. 1985-1990 ◽  
Author(s):  
Aryan Vink ◽  
Arjan H. Schoneveld ◽  
Jelger J. van der Meer ◽  
Ben J. van Middelaar ◽  
Joost P.G. Sluijter ◽  
...  
Keyword(s):  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals TREM2, Driving the Microglial Polarization, Has a TLR4 Sensitivity Profile After Subarachnoid Hemorrhage

2021 ◽  
Vol 9 ◽  
Author(s):  
Yangchun Hu ◽  
Chao Li ◽  
Xiaojian Wang ◽  
Weiwei Chen ◽  
Yu Qian ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Neuroprotective Effect ◽  
Neurological Dysfunction ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Microglial Polarization ◽  
The Relationship

Increasing evidence suggests that triggering receptor expressed on myeloid cells 2 (TREM2) is implicated in the pathophysiology of neuroinflammation. The aim here was to investigate the neuroprotective role of TREM2 and its regulatory mechanism after subarachnoid hemorrhage (SAH). TREM2 siRNA was administered to measure the detrimental role of TREM2 in mediating microglial polarization in vivo and in vitro after experimental SAH. The relationship between Toll-like receptor 4 (TLR4) signaling and TREM2 was further explored. The soluble TREM2 from the cerebrospinal fluid (CSF) of patients with SAH was detected. The results showed that TREM2 mainly located in the microglia and presented a markedly delayed elevation after SAH. TREM2 knockdown triggered increased pro-inflammatory productions, aggravated microglial activities, and further exacerbated neurological dysfunction after SAH. Significantly, TLR4 knockout increased the expression of TREM2, accompanied by ameliorated neuroinflammation and improved neurological function. Corresponding to different clinical Hunt–Hess grades, obviously enhanced accumulation of soluble TREM2 was detected in the CSF of patients with SAH. TREM2 played a pivotal role in mediating microglial polarization after SAH, and the neuroprotective effect of TREM2 might be potentially suppressed by the hyperactive TLR4 in the early phase of SAH. Pharmacological targeting of TREM2 may be a promising strategy for SAH therapy.

scholarly journals The Absence of Toll-Like Receptor 4 Signaling in C3H/HeJ Mice Predisposes Them to Overwhelming Rickettsial Infection and Decreased Protective Th1 Responses

2008 ◽  
Vol 76 (8) ◽  
pp. 3717-3724 ◽  
Author(s):  
Jeffrey M. Jordan ◽  
Michael E. Woods ◽  
Juan Olano ◽  
David H. Walker
Keyword(s):  
Rickettsia Conorii ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tlr4 Signaling ◽  
Rickettsial Infections ◽  
Factor Alpha ◽  
Intravenous Inoculation

ABSTRACT The importance of toll-like receptor 4 (TLR4) in immunity to rickettsiae remains elusive. To investigate the role of TLR4 in protection against rickettsioses, we utilized C3H/HeJ mice, which are naturally defective in TLR4 signaling, and compared the responses of C3H/HeN and C3H/HeJ mice following intravenous inoculation with Rickettsia conorii. Mice genetically defective in TLR4 signaling developed overwhelming, fatal rickettsial infections when given an inoculum that was nonfatal for TLR4-competent mice. In addition, mice lacking the ability to signal through TLR4 had significantly greater rickettsial burdens in vivo. Moreover, we observed greater concentrations of the cytokines interleukin 6 (IL-6), tumor necrosis factor alpha, IL-12p40, IL-12p70, and IL-17 in the sera of mice with intact TLR4 function as well as significantly greater quantities of activated CD4+ and CD8+ T lymphocytes. Additionally, we also observed that Th17 cells were present only in TLR4-competent mice, suggesting an important role for TLR4 ligation in the activation of this subset. In agreement with these data, we also observed significantly greater percentages of immunosuppressive regulatory T cells in the spleen during infection in TLR4-defective mice. Together, these data demonstrate that, while rickettsiae do not contain endotoxic lipopolysaccharide, they nevertheless initiate TLR4-specific immune responses, and these responses are important in protection.

scholarly journals Platelet-bound lipopolysaccharide enhances Fc receptor–mediated phagocytosis of IgG-opsonized platelets

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4803-4805 ◽  
Author(s):  
John W. Semple ◽  
Rukhsana Aslam ◽  
Michael Kim ◽  
Edwin R. Speck ◽  
John Freedman
Keyword(s):  
Flow Cytometry ◽  
Toll Like Receptor ◽  
Autoimmune Thrombocytopenia ◽  
Toll Like Receptor 4 ◽  
Platelet Destruction ◽  
Gram Negative ◽  
Synergistic Increase

Abstract Platelets express Toll-like receptor 4 (TLR4), and this has been shown to be responsible for the thrombocytopenia induced by lipopolysaccharide (LPS) administration in vivo. We studied the role of LPS in mediating platelet phagocytosis by THP-1 cells in vitro by flow cytometry. Opsonization of platelets with an IgG monoclonal (W6/32) antibody or with IgG autoantibody-positive sera from patients with autoimmune thrombocytopenia (AITP) significantly enhanced platelet phagocytosis (P < .001). In contrast, platelet phagocytosis did not occur if platelets were bound with only LPS. If, however, the LPS-bound platelets were also opsonized with either W6/32 or autoantibody-positive sera with titers greater than 4, there was a significant and synergistic increase in Fc-dependent platelet phagocytosis (P < .001, P = .003, P = .048, and P = .047). These results suggest that, in the presence of antiplatelet antibodies, bacterial products can significantly alter platelet phagocytosis, and this may have relevance to how Gram-negative infections enhance platelet destruction in some patients with AITP.

scholarly journals Endotoxaemia-augmented murine venous thrombosis is dependent on TLR-4 and ICAM-1, and potentiated by neutropenia

2017 ◽  
Vol 117 (02) ◽  
pp. 339-348 ◽  
Author(s):  
Andrea T. Obi ◽  
Elizabeth Andraska ◽  
Yogendra Kanthi ◽  
Chase W. Kessinger ◽  
Megan Elfline ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Inferior Vena ◽  
Leukocyte Adhesion ◽  
Vena Cava ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Supplementary Material ◽  
Pai 1

SummaryVenous thromboembolism is a major cause of death during and immediately post-sepsis. Venous thrombosis (VT) is mediated by cell adhesion molecules and leukocytes, including neutrophil extracellular traps (NETs). Sepsis, or experimentally, endotoxaemia, shares similar characteristics and is modulated via toll like receptor 4 (TLR4). This study was undertaken to determine if endotoxaemia potentiates early stasis thrombogenesis, and secondarily to determine the role of VT TLR4, ICAM-1 and neutrophils (PMNs). Wild-type (WT), ICAM-1-/- and TLR4-/- mice underwent treatment with saline or LPS (10 mg/kg i.p.) alone, or followed by inferior vena cava (IVC) ligation to generate stasis VT. In vivo microscopy of leukocyte trafficking was performed in non-thrombosed mice, and tissue and plasma were harvested during early VT formation. Pre-thrombosis, circulating ICAM-1 was elevated and increased leukocyte adhesion and rolling occurred on the IVC of LPS-treated mice. Post-thrombosis, endotoxaemic mice formed larger, platelet-poor thrombi. Endotoxaemic TLR4-/- mice did not have an augmented thrombotic response and exhibited significantly decreased circulating ICAM-1 compared to endotoxaemic WT controls. Endotoxaemic ICAM-1-/- mice had significantly smaller thrombi compared to controls. Hypothesising that PMNs localised to the inflamed endothelium were promoting thrombosis, PMN depletion using anti-Ly6G antibody was performed. Paradoxically, VT formed without PMNs was amplified, potentially related to endotoxaemia induced elevation of PAI-1 and circulating FXIII, and decreased uPA. Endotoxaemia enhanced early VT occurs in a TLR-4 and ICAM-1 dependent fashion, and is potentiated by neutropenia. ICAM-1 and/or TLR-4 inhibition may be a unique strategy to prevent sepsis-associated VT.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Obese Adipose Tissue Secretion Induces Inflammation in Preadipocytes: Role of Toll-Like Receptor-4

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2828 ◽  
Author(s):  
Mariana Renovato-Martins ◽  
Catharina Moreira-Nunes ◽  
Georgia C. Atella ◽  
Christina Barja-Fidalgo ◽  
João Alfredo de Moraes
Keyword(s):  
Adipose Tissue ◽  
Nuclear Translocation ◽  
Low Grade ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Proinflammatory Mediators ◽  
Low Grade Inflammation

In obesity, the dysfunctional adipose tissue (AT) releases increased levels of proinflammatory adipokines such as TNFα, IL-6, and IL-1β and free fatty acids (FFAs), characterizing a chronic, low-grade inflammation. Whilst FFAs and proinflammatory adipokines are known to elicit an inflammatory response within AT, their relative influence upon preadipocytes, the precursors of mature adipocytes, is yet to be determined. Our results demonstrated that the conditioned medium (CM) derived from obese AT was rich in FFAs, which guided us to evaluate the role of TLR4 in the induction of inflammation in preadipocytes. We observed that CM derived from obese AT increased reactive oxygen species (ROS) levels and NF-ĸB nuclear translocation together with IL-6, TNFα, and IL-1β in 3T3-L1 cells in a TLR4-dependent manner. Furthermore, TLR4 signaling was involved in the increased expression of C/EBPα together with the release of leptin, adiponectin, and proinflammatory mediators, in response to the CM derived from obese AT. Our results suggest that obese AT milieu secretes lipokines, which act in a combined paracrine/autocrine manner, inducing inflammation in preadipocytes via TLR4 and ROS, thus creating a paracrine loop that facilitates the differentiation of adipocytes with a proinflammatory profile.

scholarly journals A critical role of toll-like receptor 4 (TLR4) and its’ in vivo ligands in basal radio-resistance

2013 ◽  
Vol 4 (5) ◽  
pp. e649-e649 ◽  
Author(s):  
C Liu ◽  
C Zhang ◽  
R EJ Mitchel ◽  
J Cui ◽  
J Lin ◽  
...  
Keyword(s):  
Critical Role ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

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

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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