Faculty Opinions recommendation of Administration of a synthetic TLR4 agonist protects mice from pneumonic tularemia.

2008 ◽  
Author(s):  
Jerrold Weiss
Keyword(s):  
Tlr4 Agonist

scholarly journals Regulation of CAMP (cathelicidin antimicrobial peptide) expression in adipocytes by TLR 2 and 4

2021 ◽  
Vol 27 (2) ◽  
pp. 184-191
Author(s):  
Alexandra Höpfinger ◽  
Thomas Karrasch ◽  
Andreas Schäffler ◽  
Andreas Schmid
Keyword(s):  
Signal Transduction ◽  
Antimicrobial Peptide ◽  
Drug Targets ◽  
Specific Effect ◽  
Potent Inducer ◽  
Regulatory Circuits ◽  
Signal Transduction Inhibitors ◽  
Tlr4 Agonist ◽  
Future Drug ◽  
Regulatory Effects

Recent data argue for a pro-inflammatory role of CAMP (cathelicidin antimicrobial peptide) in adipocytes and adipose tissue (AT) and for regulatory circuits involving TLRs. In order to investigate regulatory effects of TLR2 and TLR4, 3T3-L1 adipocytes were stimulated with TLR2 agonistic lipopeptide MALP-2 and with TLR4 agonist LPS in presence or absence of signal transduction inhibitors. CAMP gene expression was analysed by quantitative real-time PCR in adipocytes and in murine AT compartments and cellular subfractions. CAMP expression was higher in gonadal than in subcutaneous AT and there was a gender-specific effect with higher levels in males. Adipocytes had higher CAMP expression than the stroma-vascular cell (SVC) fraction. MALP-2 up-regulated CAMP expression significantly, mediated by STAT3 and PI3K and potentially (non-significant trend) by NF-κB and MAPK, but not by raf-activated MEK-1/-2. Moreover, LPS proved to act as a potent inducer of CAMP via NF-κB, PI3K and STAT3, whereas specific inhibition of MAPK and MEK-1/-2 had no effect. In conclusion, activation of TLR2 and TLR4 by classical ligands up-regulates adipocyte CAMP expression involving classical signal transduction elements. These might represent future drug targets for pharmacological modulation of CAMP expression in adipocytes, especially in the context of metabolic and infectious diseases.

scholarly journals Adsorption of Toll-Like Receptor 4 Agonist to Alum-Based Tetanus Toxoid Vaccine Dampens Pro-T Helper 2 Activities and Enhances Antibody Responses

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Juliana Bortolatto ◽  
Luciana Mirotti ◽  
Dunia Rodriguez ◽  
Eliane Gomes ◽  
Momtchilo Russo
Keyword(s):  
Tetanus Toxoid ◽  
Lipid A ◽  
Antibody Responses ◽  
Aluminum Salts ◽  
T Helper 2 ◽  
Monophosphoryl Lipid A ◽  
Tlr4 Agonist ◽  
Specific Antibody Production ◽  
Humoral Responses

Aluminum salts gels (alum) are TLR-independent adjuvants and have been used to boost antibody responses in alum-based vaccines such as diphtheria, pertussis, and tetanus toxoid (DPT) triple vaccine. However, the pro-Th2 activity of alum-based vaccine formulations has not been fully appreciated. Here we found that alum-based tetanus toxoid (TT) vaccine was biased toward a Th-2 profile as shown by TT-induced airway eosinophilic inflammation, type 2 cytokine production, and high levels of IgE anaphylactic antibodies. The adsorption into alum of prototypic TLR4 agonists such as lipopolysaccharides (LPS) derived fromEscherichia coliconsistently dampened TT-induced Th2 activities without inducing IFNγor Th1-like responses in the lung. Conversely, adsorption of monophosphoryl lipid A (MPLA) extracted fromSalmonella minnesota, which is a TIR-domain-containing adapter-inducing interferon-β- (TRIF-) biased TLR4 agonist, was less effective in decreasing Th-2 responses. Importantly, in a situation with antigenic competition (OVA plus TT), TT-specific IgG1 or IgG2a was decreased compared with TT sensitization. Notably, LPS increased the production of IgG1 and IgG2a TT-specific antibodies. In conclusion, the addition of LPS induces a more robust IgG1 and IgG2a TT-specific antibody production and concomitantly decreases Th2-cellular and humoral responses, indicating a potential use of alum/TLR-based vaccines.

Bet v 1 contiguous overlapping peptides anchored to virosomes with TLR4 agonist enhance immunotherapy efficacy in mice

2021 ◽  
Author(s):  
Sabi Airouche ◽  
Vanya Beltrami ◽  
Sylvain Fleury ◽  
Thierry Batard ◽  
Véronique Bordas‐Le Floch ◽  
...  
Keyword(s):  
Bet V 1 ◽  
Tlr4 Agonist

Goblet Cell Hyperplasia is not Epithelial-Autonomous in the Cftr Knockout Intestine

2021 ◽  
Author(s):  
Nancy M Walker ◽  
Jinghua Liu ◽  
Sarah M Young ◽  
Rowena A Woode ◽  
Lane L. Clarke
Keyword(s):  
Cell Differentiation ◽  
Goblet Cell ◽  
Ex Vivo ◽  
Cell Hyperplasia ◽  
Goblet Cell Hyperplasia ◽  
Cell Numbers ◽  
Markers Of Inflammation ◽  
Tlr4 Agonist ◽  
Goblet Cell Differentiation ◽  
Mucosal Morphology

Goblet cell hyperplasia is an important manifestation of cystic fibrosis (CF) disease in epithelial-lined organs. Explants of CF airway epithelium show normalization of goblet cell numbers; therefore we hypothesized that small intestinal enteroids from Cftr knockout (KO) mice would not exhibit goblet cell hyperplasia. Toll-like receptors 2 and 4 (Tlr2, Tlr4) were investigated as markers of inflammation and influence on goblet cell differentiation. Ex vivo studies found goblet cell hyperplasia in Cftr KO jejunum as compared to wild-type (WT). IL-13, SAM pointed domain-containing ETS transcription factor (Spdef), Tlr2 and Tlr4 protein expression was increased in Cftr KO intestine relative to WT. In contrast, WT and Cftr KO enteroids did not exhibit differences in basal or IL-13-stimulated goblet cell numbers, or differences in expression of Tlr2, Tlr4 and Spdef. Ileal goblet cell numbers in Cftr KO/Tlr4 KO and Cftr KO/Tlr2 KO mice were not different from Cftr KO mice, but enumeration was confounded by altered mucosal morphology. Treatment with Tlr4 agonist LPS did not affect goblet cell numbers in WT or Cftr KO enteroids, whereas the Tlr2 agonist Pam3Csk4 stimulated goblet cell hyperplasia in both genotypes. Pam3Csk4 stimulation of goblet cell numbers was associated with suppression of Notch1 and Neurog3 expression and upregulated determinants of goblet cell differentiation. We conclude that goblet cell hyperplasia and inflammation of the Cftr KO small intestine are not exhibited by enteroids, indicating that this manifestation of CF intestinal disease is not epithelial-automatous but secondary to the altered CF intestinal environment.

scholarly journals Bacterial outer membrane vesicles engineered with lipidated antigens as a platform for Staphylococcus aureus vaccine

2019 ◽  
Vol 116 (43) ◽  
pp. 21780-21788 ◽  
Author(s):  
Carmela Irene ◽  
Laura Fantappiè ◽  
Elena Caproni ◽  
Francesca Zerbini ◽  
Andrea Anesi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Outer Membrane ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Vaccine Platform ◽  
Transport Pathway ◽  
Protective Antigens ◽  
Tlr4 Agonist ◽  
Engineering Strategy ◽  
Bacterial Outer Membrane

Bacterial outer membrane vesicles (OMVs) represent an interesting vaccine platform for their built-in adjuvanticity and simplicity of production process. Moreover, OMVs can be decorated with foreign antigens using different synthetic biology approaches. However, the optimal OMV engineering strategy, which should guarantee the OMV compartmentalization of most heterologous antigens in quantities high enough to elicit protective immune responses, remains to be validated. In this work we exploited the lipoprotein transport pathway to engineer OMVs with foreign proteins. Using 5 Staphylococcus aureus protective antigens expressed in Escherichia coli as fusions to a lipoprotein leader sequence, we demonstrated that all 5 antigens accumulated in the vesicular compartment at a concentration ranging from 5 to 20% of total OMV proteins, suggesting that antigen lipidation could be a universal approach for OMV manipulation. Engineered OMVs elicited high, saturating antigen-specific antibody titers when administered to mice in quantities as low as 0.2 μg/dose. Moreover, the expression of lipidated antigens in E. coli BL21(DE3)ΔompAΔmsbBΔpagP was shown to affect the lipopolysaccharide structure, with the result that the TLR4 agonist activity of OMVs was markedly reduced. These results, together with the potent protective activity of engineered OMVs observed in mice challenged with S. aureus Newman strain, makes the 5-combo-OMVs a promising vaccine candidate to be tested in clinics.

MF59 Emulsion Is an Effective Delivery System for a Synthetic TLR4 Agonist (E6020)

2009 ◽  
Vol 26 (6) ◽  
pp. 1477-1485 ◽  
Author(s):  
Barbara C. Baudner ◽  
Vanessa Ronconi ◽  
Daniele Casini ◽  
Marco Tortoli ◽  
Jina Kazzaz ◽  
...  
Keyword(s):  
Delivery System ◽  
Tlr4 Agonist ◽  
Effective Delivery

scholarly journals NF-κB mediates lipopolysaccharide-induced alternative pre-mRNA splicing of MyD88 in mouse macrophages

2020 ◽  
Vol 295 (18) ◽  
pp. 6236-6248
Author(s):  
Frank Fang-Yao Lee ◽  
Kevin Davidson ◽  
Chelsea Harris ◽  
Jazalle McClendon ◽  
William J. Janssen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Chronic Inflammation ◽  
Mrna Splicing ◽  
Dominant Negative ◽  
Mrna Isoforms ◽  
Inflammatory Signaling ◽  
Tlr Signaling ◽  
Tlr4 Agonist ◽  
Alternatively Spliced ◽  
Tlr Signaling Pathway

Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. Whereas most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that 1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, 2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, 3) MyD88 splicing is regulated by the NF-κB transcription factor, and 4) NF-κB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled.

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