Therapeutic targeting of innate immunity with Toll-like receptor 4 (TLR4) antagonists

Peri, Francesco; Piazza, Matteo

doi:10.1016/j.biotechadv.2011.05.014

Cited by 140 publications

(129 citation statements)

References 88 publications

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“…In addition to lowered toxicity important for expression and gene therapy strains, some lipid A species from the library could possess antagonistic properties that inhibit TLR4 signaling. As antisepsis drugs, they could serve to block the strong inflammatory response during to septic shock (34). In this work, we have followed a synthetic lipid biology approach to generate a combinatorial library of lipid A molecules to satisfy a wide array of biotechnological and therapeutic needs, the scope of which will continue to broaden as further investigation into the potential of these strains is completed.…”

Section: Discussionmentioning

confidence: 99%

Modulating the innate immune response by combinatorial engineering of endotoxin

Needham

Carroll²,

Giles

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

184

219

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Despite its highly inflammatory nature, LPS is a molecule with remarkable therapeutic potential. Lipid A is a glycolipid that serves as the hydrophobic anchor of LPS and constitutes a potent ligand of the Toll-like receptor (TLR)4/myeloid differentiation factor 2 receptor of the innate immune system. A less toxic mixture of monophosphorylated lipid A species (MPL) recently became the first new Food and Drug Administration-approved adjuvant in over 70 y. Whereas wild-type Escherichia coli LPS provokes strong inflammatory MyD88 (myeloid differentiation primary response gene 88)-mediated TLR4 signaling, MPL preferentially induces less inflammatory TRIF (TIR-domain-containing adaptor-inducing IFN-β)-mediated responses. Here, we developed a system for combinatorial structural diversification of E. coli lipid A, yielding a spectrum of bioactive variants that display distinct TLR4 agonist activities and cytokine induction. Mice immunized with engineered lipid A/antigen emulsions exhibited robust IgG titers, indicating the efficacy of these molecules as adjuvants. This approach demonstrates how combinatorial engineering of lipid A can be exploited to generate a spectrum of immunostimulatory molecules for vaccine and therapeutics development.

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Section: Discussionmentioning

confidence: 99%

Modulating the innate immune response by combinatorial engineering of endotoxin

Needham

Carroll²,

Giles

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

184

219

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“…Because CD14 is potentially a target of a new generation of antisepsis agents (77), the finding that Fh12 targets the CD14 co-receptor could have pharmacological applications. A glycoconjugate preparation from Treponema spirochetes (Tm-Gp) was also reported to inhibit the interaction of LPS with CD14, acting as an antagonist of TLR4 (78); however, this preparation is chemically heterogeneous and it was not possible to determine the component responsible for the interaction.…”

Section: Discussionmentioning

confidence: 99%

Fasciola hepaticaFatty Acid Binding Protein Inhibits TLR4 Activation and Suppresses the Inflammatory Cytokines Induced by Lipopolysaccharide In Vitro and In Vivo

Martin

Cabán-Hernández

Figueroa-Santiago

et al. 2015

The Journal of Immunology

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Toll-like receptor 4 (TLR4), the innate immunity receptor for bacterial endotoxins, plays a pivotal role in the induction of inflammatory responses. There is a need to develop molecules that block either activation through TLR4 or the downstream signaling pathways to inhibit the storm of inflammation typically elicited by bacterial lipopolysaccharide (LPS), which is a major cause of the high mortality associated with bacterial sepsis. We report here that a single intraperitoneal injection of 15μg Fasciola hepatica fatty acid binding protein (Fh12) 1 hour before exposure to LPS suppressed significantly the expression of serum inflammatory cytokines in a model of septic shock using C57BL/6 mice. Because macrophages are good source of IL12p70 and TNFα, and critical in driving adaptive immunity, we investigated the effect of Fh12 on the function of mouse bone marrow derived macrophages (bmMΦs). Whereas Fh12 alone did not induce cytokine expression, it significantly suppressed the expression of IL12, TNFα, IL6 and IL1β cytokines as well as iNOS2 in bmMΦs, and also impaired the phagocytic capacity of bmMΦs. Fh12 had a limited effect on the expression of inflammatory cytokines induced in response to other TLR-ligands. One mechanism used by Fh12 to exert its anti-inflammatory effect is binding to the CD14 co-receptor. Moreover, it suppresses phosphorylation of ERK, p38 and JNK. The potent anti-inflammatory properties of Fh12 demonstrated here open doors to further studies directed at exploring the potential of this molecule as a new class of drug against septic shock or other inflammatory diseases.

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“…Inflammation is a key detrimental component of myocardial ischemia-reperfusion injury [7] and TLRs are important components of the innate immunity response to pathogens as well as non-pathogenic components of damaged tissues. Accordingly, TLRs are involved in the pathogenesis of atherosclerosis, thrombosis, and ischemic/reperfusion injury [8-10]. Hence, TLR antagonists may be used therapeutically for a number of inflammatory conditions [11].…”

Section: Discussionmentioning

confidence: 99%

Sparstolonin B Attenuates Hypoxia-Induced Apoptosis, Necrosis and Inflammation in Cultured Rat Left Ventricular Tissue Slices

Liu

Jubair

et al. 2014

Cardiovasc Drugs Ther

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Purpose Ischemia/reperfusion results in tissue damage, a rapid increase in cytokines and chemokines and inflammatory cell infiltration. Herein we investigated the ability of a selective TLR2/4 antagonist, Sparstolonin B (SsnB), to protect rat cultured left ventricular tissue (LV) slices from hypoxic injury by inhibiting the myocardial inflammatory response independent of inflammatory cell infiltration. Methods and Results Media Lactate dehydrogenase (LDH) levels were measured to reflect hypoxia-induced cytotoxicity and cell injury with and without SsnB. Incubation with SsnB (15 and 30 μM) significantly reduced by 20 and 40 %, respectively, the amount of LDH released from the hypoxic LV slices. TUNEL staining showed that SsnB significantly attenuated the levels of hypoxia-induced apoptotic cells from 61.5 ±4.0 to 27.0±2.1 (15 μM SsnB) and 23.5±2.2 (30 μM SsnB) cells/unit area. Similarly, the Periodic Acid-Schiff (PAS) staining of ischemic areas in untreated hypoxic LV slices was increased 17 fold from 0.26±0.09 to 4.41±0.43 %, while in hypoxic slices incubated with 15 and 30 μM of SsnB, the PAS positive ischemic areas were increased by only 6.4 fold to 1.66±0.39 % and 3.8 fold to 1.00±0.22 %, respectively. Rt-PCR confirmed that MCP1 and IL-6 expression during hypoxia was elevated by 2 and 4 fold, respectively, while their upregulation was significantly inhibited (i.e., <0.7 fold increase) by SsnB. Conclusion The selective TLR2/4 antagonist, Sparstolonin B, can substantially protect LV myocardium via its ability to inhibit injury resulting from hypoxic myocardial-generated inflammation. Accordingly SsnB has potential as a therapeutic agent for the attenuation of myocardial ischemia-reperfusion injury.

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Therapeutic targeting of innate immunity with Toll-like receptor 4 (TLR4) antagonists

Cited by 140 publications

References 88 publications

Modulating the innate immune response by combinatorial engineering of endotoxin

Modulating the innate immune response by combinatorial engineering of endotoxin

Fasciola hepaticaFatty Acid Binding Protein Inhibits TLR4 Activation and Suppresses the Inflammatory Cytokines Induced by Lipopolysaccharide In Vitro and In Vivo

Sparstolonin B Attenuates Hypoxia-Induced Apoptosis, Necrosis and Inflammation in Cultured Rat Left Ventricular Tissue Slices

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