Monophosphoryl lipid a attenuates radiation injury through TLR4 activation

Guo, Jiaming; Chen, Yuanyuan; Xiao, Lanbo; Xu, Yang; Liu, Zhe; Cai, Jianming; Fu, Guosheng; Yang, Yue

doi:10.18632/oncotarget.20907

Cited by 16 publications

(14 citation statements)

References 29 publications

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“…The agonist-activated TLR4 transfers its signal via the myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways, and the toll-interleukin 1 receptor domain-containing adapter inducing interferon-beta (TRIFF)–involved pathway ( 27 , 28 ). Although LPS activates both MyD88 and TRIFF, several reports demonstrate that the action of MPLA is more dependent on TRIFF than LPS, which induces strong activation of the MyD88 pathway ( 29 , 30 ). TLR4 is associated with cell death by TRIFF activation ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells

Lee

Kashif

et al. 2020

Front. Immunol.

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S100A8 and S100A9 function as essential factors in inflammation and also exert antitumor or tumorigenic activity depending on the type of cancer. Chronic eosinophilic leukemia (CEL) is a rare hematological malignancy having elevated levels of eosinophils and characterized by the presence of the FIP1L1-PDGFRA fusion gene. In this study, we examined the pro-apoptotic mechanisms of S100A8 and S100A9 in FIP1L1-PDGFRα+ eosinophilic cells and hypereosinophilic patient cells. S100A8 and S100A9 induce apoptosis of the FIP1L1-PDGFRα+ EoL-1 cells via TLR4. The surface TLR4 expression increased after exposure to S100A8 and S100A9 although total TLR4 expression decreased. S100A8 and S100A9 suppressed the FIP1L1-PDGFRα-mediated signaling pathway by downregulating FIP1L1-PDGFRα mRNA and protein expression and triggered cell apoptosis by regulating caspase 9/3 pathway and Bcl family proteins. S100A8 and S100A9 also induced apoptosis of imatinib-resistant EoL-1 cells (EoL-1-IR). S100A8 and S100A9 blocked tumor progression of xenografted EoL-1 and EoL-1-IR cells in NOD-SCID mice and evoked apoptosis of eosinophils derived from hypereosinophilic syndrome as well as chronic eosinophilic leukemia. These findings may contribute to a progressive understanding of S100A8 and S100A9 in the pathogenic and therapeutic mechanism of hematological malignancy.

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Section: Discussionmentioning

confidence: 99%

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells

Lee

Kashif

et al. 2020

Front. Immunol.

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“…As a radiosensitive organ, the small intestine is prone to the radiation damage [10–12]. It is indicated that toll-like receptors (TLRs) are associated with the basal resistance to IR [2]. The agonists or ligands of TLRs are potentially radioprotective, while most of them are limited to animal experiment because of the severe toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Burdelya et al reported that TLR5 agonist CBLB502 effectively mitigated gastrointestinal and haematopoietic radiation injury in both mice and monkeys [1]. Moreover, we have demonstrated that TLR4 played a critical role in basal radioresistance by activating the NF- κ B signaling pathway [2]. And lipopolysaccharide (LPS), a classic TLR4 ligand, effectively protected intestinal injury through cyclooxygenase-2 (Cox-2) with the induction of prostaglandin E2 (PGE2) synthesis [3].…”

Section: Introductionmentioning

confidence: 99%

TLR4 Agonist Monophosphoryl Lipid A Alleviated Radiation-Induced Intestinal Injury

Guo¹,

Liu²,

Zhang

et al. 2019

Journal of Immunology Research

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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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“…Because of its immunostimulating activity and the lack of toxicity, the use of MPLA has been envisaged in a wide array of clinical settings. In a recent study it has been hypothesized that MPLA stimulatory activity on the innate immune system could mitigate the radiation injury provoked by ionizing radiation (IR) in cancer radiotherapy ( 24 ). Pre-treatment with MPLA prevented IR-provoked cell apoptosis in vitro and effectively attenuated tissue damage in vivo .…”

Section: Glycolipid-based Tlr4 Modulatorsmentioning

confidence: 99%

Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview

Romerio

Peri

2020

Front. Immunol.

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Toll-Like Receptor 4 (TLR4) is one of the receptors of innate immunity. It is activated by Pathogen- and Damage-Associated Molecular Patterns (PAMPs and DAMPs) and triggers pro-inflammatory responses that belong to the repertoire of innate immune responses, consequently protecting against infectious challenges and boosting adaptive immunity. Mild TLR4 stimulation by non-toxic molecules resembling its natural agonist (lipid A) provided efficient vaccine adjuvants. The non-toxic TLR4 agonist monophosphoryl lipid A (MPLA) has been approved for clinical use. This suggests the development of other TLR4 agonists as adjuvants or drugs for cancer immunotherapy. TLR4 excessive activation by a Gram-negative bacteria lipopolysaccharide (LPS) leads to sepsis, while TLR4 stimulation by DAMPs is a common mechanism in several inflammatory and autoimmune diseases. TLR4 inhibition by small molecules and antibodies could therefore provide access to innovative therapeutics targeting sepsis as well as acute and chronic inflammations. The potential use of TLR4 antagonists as anti-inflammatory drugs with unique selectivity and a new mechanism of action compared to corticosteroids or other non-steroid anti-inflammatory drugs fueled the search for compounds of natural or synthetic origin able to block or inhibit TLR4 activation and signaling. The wide spectrum of clinical settings to which TLR4 inhibitors can be applied include autoimmune diseases (rheumatoid arthritis, inflammatory bowel diseases), vascular inflammation, neuroinflammations, and neurodegenerative diseases. The last advances (from 2017) in TLR4 activation or inhibition by small molecules (molecular weight <2 kDa) are reviewed here. Studies on pre-clinical validation of new chemical entities (drug hits) on cellular or animal models as well as new clinical studies on previously developed TLR4 modulators are reported. Innovative TLR4 modulators discovered by computer-assisted drug design and an artificial intelligence approach are described. Some “old” TLR4 agonists or antagonists such as MPLA or Eritoran are under study for repositioning in different pharmacological contexts. The mechanism of action of the molecules and the level of TLR4 involvement in their biological activity are critically discussed.

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Monophosphoryl lipid a attenuates radiation injury through TLR4 activation

Cited by 16 publications

References 29 publications

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells

S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells

TLR4 Agonist Monophosphoryl Lipid A Alleviated Radiation-Induced Intestinal Injury

Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview

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