The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism

Induction of antigen-specific cell-mediated immunity (CMI), as well as humoral immunity, is critical for successful vaccination against various type of pathogens. Toll-like receptor (TLR) agonists have been developed as adjuvants to promote vaccine efficacy and induce appropriate immune responses. Monophosphoryl lipid A (MPL); a TLR4 agonist, and Poly I:C; a TLR3 agonist, are known as a strong immuno-stimulator which induce Th1 response. Many studies proved and compared the efficacy of each adjuvant, but no study has investigated the combination of them. Using ovalbumin protein antigen, MPL+Poly I:C combination induced more effective antigen-specific CMI response than single adjuvants. Production of inflammatory cytokines, recruitment of innate immune cells and antigen-specific CD4/CD8 memory T cell at the immunized site had been significantly enhanced by MPL+Poly I:C combination. Moreover, MPL+Poly I:C combination enhanced ovalbumin-specific serum IgG, IgG1, and IgG2c production and proliferative function of CD4 and CD8 T cells after in vitro ovalbumin peptide stimulation. Taken together, these data suggest that the combination of MPL and Poly I:C has a potency as a CMI-inducing vaccine adjuvant with synergistically increased effects.

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TLR4 Agonist Monophosphoryl Lipid A Alleviated Radiation-Induced Intestinal Injury

Journal of Immunology Research ◽

10.1155/2019/2121095 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Jiaming Guo ◽

Zhe Liu ◽

Danfeng Zhang ◽

Yuanyuan Chen ◽

Hongran Qin ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Lipid A ◽

The Novel ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Irradiation Injury ◽

Tlr4 Agonist ◽

Radiation Induced ◽

Low Toxicity

The small intestine is one of the most sensitive organs to irradiation injury, and the development of high effective radioprotectants especially with low toxicity for intestinal radiation sickness is urgently needed. Monophosphoryl lipid A (MPLA) was found to be radioprotective in our previous study, while its effect against the intestinal radiation injury remained unknown. In the present study, we firstly determined the intestinal apoptosis after irradiation injury according to the TUNEL assay. Subsequently, we adopted the immunofluorescence technique to assess the expression levels of different biomarkers including Ki67, γ-H2AX, and defensin 1 in vivo. Additionally, the inflammatory cytokines were detected by RT-PCR. Our data indicated that MPLA could protect the intestine from ionizing radiation (IR) damage through activating TLR4 signal pathway and regulating the inflammatory cytokines. This research shed new light on the protective effect of the novel TLR4 agonist MPLA against intestine detriment induced by IR.

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Pre-treatment of C57BL6/J mice with the TLR4 agonist monophosphoryl lipid A prevents LPS-induced sickness behaviors and elevations in dorsal hippocampus interleukin-1β, independent of interleukin-4 expression

Behavioural Brain Research ◽

10.1016/j.bbr.2016.01.012 ◽

2016 ◽

Vol 302 ◽

pp. 171-174 ◽

Cited By ~ 3

Author(s):

M.J. Eimerbrink ◽

D. Kranjac ◽

C. St. Laurent ◽

J.D. White ◽

M.K. Weintraub ◽

...

Keyword(s):

Lipid A ◽

Dorsal Hippocampus ◽

Interleukin 1Β ◽

Interleukin 4 ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Sickness Behaviors ◽

Tlr4 Agonist ◽

Pre Treatment

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Faculty Opinions recommendation of The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4.

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

10.3410/f.1087287.540302 ◽

2007 ◽

Author(s):

Rino Rappuoli

Keyword(s):

Lipid A ◽

Vaccine Adjuvant ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Biased Agonist

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

Journal of Immunology Research ◽

10.1155/2015/280238 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 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.

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Monophosphoryl lipid A: an effective adjuvant for potentiating mucosal immune responses

Journal of Endotoxin Research ◽

10.1177/09680519990050030305 ◽

1999 ◽

Vol 5 (3) ◽

pp. 181-182 ◽

Cited By ~ 3

Author(s):

Suzanne M. Michalek ◽

Noel K. Childers ◽

Terry Greenway ◽

George Hajishengallis ◽

J. Terry Ulrich

Keyword(s):

Immune Responses ◽

Lipid A ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Mucosal Immune Responses

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Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through a TLR4-TRIF-PI3K signaling pathway

AJP Renal Physiology ◽

10.1152/ajprenal.00064.2017 ◽

2017 ◽

Vol 313 (1) ◽

pp. F103-F115 ◽

Cited By ~ 10

Author(s):

Bruns A. Watts ◽

Thampi George ◽

Edward R. Sherwood ◽

David W. Good

Keyword(s):

Bacterial Infections ◽

Lipid A ◽

Thick Ascending Limb ◽

Akt Inhibitor ◽

Erk Activation ◽

Akt Phosphorylation ◽

Medullary Thick Ascending Limb ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid

Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that induces tolerance to LPS and augments host resistance to bacterial infections. Previously, we demonstrated that LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a basolateral Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-ERK pathway. Here we examined whether pretreatment with MPLA would attenuate LPS inhibition. MTALs from rats were perfused in vitro with MPLA (1 µg/ml) in bath and lumen or bath alone for 2 h, and then LPS was added to (and MPLA removed from) the bath solution. Pretreatment with MPLA eliminated LPS-induced inhibition of [Formula: see text] absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3-kinase (PI3K) or Akt inhibitor, LPS decreased [Formula: see text] absorption. MPLA increased Akt phosphorylation in dissected MTALs. The Akt activation was eliminated by a PI3K inhibitor and in MTALs from TLR4−/−or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)−/−mice. The effect of MPLA to prevent LPS inhibition of [Formula: see text] absorption also was TRIF dependent. Pretreatment with MPLA prevented LPS-induced ERK activation; this effect was dependent on PI3K. MPLA alone had no effect on [Formula: see text] absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of [Formula: see text] absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate that pretreatment with MPLA prevents the effect of LPS to inhibit [Formula: see text] absorption in the MTAL. This protective effect is mediated directly through MPLA stimulation of a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. These studies identify detoxified TLR4-based immunomodulators as novel potential therapeutic agents to prevent or treat renal tubule dysfunction in response to bacterial infections.

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