Inhibitions of HMGB1 and TLR4 alleviate DINP-induced asthma in mice

Hwang, Yunho; Lee, Yongjin; Paik, Man‐Jeong; Yee, Sung‐Tae

doi:10.1039/c9tx00048h

Cited by 27 publications

(13 citation statements)

References 33 publications

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“…Inadequate regulation of the TLR4 signaling contributes to the pathogenesis of a number of acute and chronic inflammatory as well as autoimmune diseases such as allergy, arthritis (7)(8)(9), asthma (10)(11)(12), cardiovascular disorders (13), Alzheimer disease-associated pathology (14) and systemic inflammatory response syndrome (SIRS) and septic shock (15,16). Impressive research demonstrated that down-regulation of the TLR4 mediated signaling can be useful for therapeutic benefits and efficient for management of asthma (17,18), arthritis, (8) viral infections [influenza (19) and Ebola virus (20)], cancer (21), and sepsis (22). Besides, TLR4-mediated signaling has been demonstrated to promote dendritic cells maturation thereby linking innate and adaptive immunity (23,24) which features activation of the TLR4/MD-2 complex by TLR4-specific ligands of low toxicity as facile approach for development of novel vaccine adjuvants (25)(26)(27).…”

Section: Lipopolysaccharide Detection By the Innate Immune Systemmentioning

confidence: 99%

“…One of the plausible mechanisms for LPS internalization and intracellular delivery involves LPS binding by high-mobility group box 1 (HMGB1) -an alarmin which can efficiently transport LPS into the cytoplasm through receptor for advanced glycation end products (RAGE)-mediated endocytosis (17,135,136). Through internalization of HMGB1-LPS complexes mediated by RAGE, HMGB1 induces destabilization of lysosomes for cytosolic LPS delivery.…”

Section: Cytosolic Delivery Of Lps For Noncanonical Inflammasome Actimentioning

confidence: 99%

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Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

2020

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The innate immune response to lipopolysaccharide is essential for host defense against Gram-negative bacteria. In response to bacterial infection, the TLR4/MD-2 complex that is expressed on the surface of macrophages, monocytes, dendritic, and epithelial cells senses picomolar concentrations of endotoxic LPS and triggers the production of various pro-inflammatory mediators. In addition, LPS from extracellular bacteria which is either endocytosed or transfected into the cytosol of host cells or cytosolic LPS produced by intracellular bacteria is recognized by cytosolic proteases caspase-4/11 and hosts guanylate binding proteins that are involved in the assembly and activation of the NLRP3 inflammasome. All these events result in the initiation of pro-inflammatory signaling cascades directed at bacterial eradication. However, TLR4-mediated signaling and caspase-4/11-induced pyroptosis are largely involved in the pathogenesis of chronic and acute inflammation. Both extra- and intracellular LPS receptors—TLR4/MD-2 complex and caspase-4/11, respectively—are able to directly bind the lipid A motif of LPS. Whereas the structural basis of lipid A recognition by the TLR4 complex is profoundly studied and well understood, the atomic mechanism of LPS/lipid A interaction with caspase-4/11 is largely unknown. Here we describe the LPS-induced TLR4 and caspase-4/11 mediated signaling pathways and their cross-talk and scrutinize specific structural features of the lipid A motif of diverse LPS variants that have been reported to activate caspase-4/11 or to induce caspase-4/11 mediated activation of NLRP3 inflammasome (either upon transfection of LPS in vitro or upon infection of cell cultures with intracellular bacteria or by LPS as a component of the outer membrane vesicles). Generally, inflammatory caspases show rather similar structural requirements as the TLR4/MD-2 complex, so that a “basic” hexaacylated bisphosphorylated lipid A architecture is sufficient for activation. However, caspase-4/11 can sense and respond to much broader variety of lipid A variants compared to the very “narrow” specificity of TLR4/MD-2 complex as far as the number and the length of lipid chains attached at the diglucosamine backbone of lipid A is concerned. Besides, modification of the lipid A phosphate groups with positively charged appendages such as phosphoethanolamine or aminoarabinose could be essential for the interaction of lipid A/LPS with inflammatory caspases and related proteins.

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Section: Lipopolysaccharide Detection By the Innate Immune Systemmentioning

confidence: 99%

Section: Cytosolic Delivery Of Lps For Noncanonical Inflammasome Actimentioning

confidence: 99%

Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

2020

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“…Toll like receptor signaling pathway was activated in patients in the exacerbation group. In fact, the complex interaction between environmental allergens and TLRs results in In the hub genes, TLR4 was reported to be signi cantly associated with the occurrence and development of asthma (Hwang, et al 2019). Heat shock protein (HSP) played a major role in promoting in ammation and anti-in ammatory response (Hallenbeck and Kaplan 1987).…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between Gene Expression Pattern and the Severity of Asthma

Lin¹,

Luo²,

Cheng³

et al. 2020

Preprint

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Background Because of heterogeneity, complexity of diagnosis and diversity of pathogenesis, the incidence and mortality of asthma are increased seriously. A structured and specific approach to assess and treat asthma may help clinicians. Results A total of 838 common genes were found from quietness to exacerbation then to recovery of asthma. PPI network analysis identified 7 modules, and found 7 hub genes with high degree. Then, we verified the expression of hub genes in patients by quantitative real-time polymerase chain reaction (qRT-PCR). Enrichment analysis and gene set enrichment analysis (GSEA) showed that exacerbation related genes were significantly related to immune and inflammatory response. Transcriptional regulators factor STAT1 had a significant regulatory effect on exacerbation related genes. Conclusions These results indicated that seven hub genes were potential biomarkers and targets of asthma exacerbation. they were involved in the development of asthma through immune inflammatory signaling pathway. The results of this study not only provide a new research direction and theoretical basis for the exacerbation mechanism of asthma, but also provide a new target for clinical treatment.

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“…Targeting HMGB1 may a useful treatment for asthma. HMGB1 antagonists repressed leukocyte infiltration, levels of collagen, cell counts and pro-inflammatory cytokines in animal models, which attenuated airway remodeling and airway hyperresponsiveness [ 204 , 205 , 206 ].…”

Section: Role Of Hmgb1 In Various Inflammatory Disordersmentioning

confidence: 99%

The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

Huang

Yao

2021

Cells

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High mobility group box-1 protein (HMGB1), a member of the high mobility group protein superfamily, is an abundant and ubiquitously expressed nuclear protein. Intracellular HMGB1 is released by immune and necrotic cells and secreted HMGB1 activates a range of immune cells, contributing to the excessive release of inflammatory cytokines and promoting processes such as cell migration and adhesion. Moreover, HMGB1 is a typical damage-associated molecular pattern molecule that participates in various inflammatory and immune responses. In these ways, it plays a critical role in the pathophysiology of inflammatory diseases. Herein, we review the effects of HMGB1 on various immune cell types and describe the molecular mechanisms by which it contributes to the development of inflammatory disorders. Finally, we address the therapeutic potential of targeting HMGB1.

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Inhibitions of HMGB1 and TLR4 alleviate DINP-induced asthma in mice

Cited by 27 publications

References 33 publications

Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways

The Relationship Between Gene Expression Pattern and the Severity of Asthma

The Effect and Regulatory Mechanism of High Mobility Group Box-1 Protein on Immune Cells in Inflammatory Diseases

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