Folic acid derived-P5779 mimetics regulate DAMP-mediated inflammation through disruption of HMGB1:TLR4:MD-2 axes

Sun, Shan; He, Mingzhu; Wang, Yongjun; Yang, Huan; Al‐Abed, Yousef

doi:10.1371/journal.pone.0193028

Cited by 18 publications

(14 citation statements)

References 26 publications

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“…P5779 treatment conferred a striking survival advantage in an experimental pulmonary arterial hypertension model (47). Using a molecular dynamic simulation approach and surface plasmon resonance analysis, Sun et al (48) identified that several folic acid peptides mimic the binding interaction of P5779 at the TLR4/MD-2 interaction. Addition of these P5779 mimetic peptides inhibited HMGB1-induced TNF release in cultured human macrophages.…”

Section: Peptide P5779mentioning

confidence: 99%

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Targeting Inflammation Driven by HMGB1

2020

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High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and outside of cells. Extracellular HMGB1 has been extensively studied for its prototypical alarmin functions activating innate immunity, after being actively released from cells or passively released upon cell death. TLR4 and RAGE operate as the main HMGB1 receptors. Disulfide HMGB1 activates the TLR4 complex by binding to MD-2. The binding site is separate from that of LPS and it is now feasible to specifically interrupt HMGB1/TLR4 activation without compromising protective LPS/TLR4-dependent functions. Another important therapeutic strategy is established on the administration of HMGB1 antagonists precluding RAGE-mediated endocytosis of HMGB1 and HMGB1-bound molecules capable of activating intracellular cognate receptors. Here we summarize the role of HMGB1 in inflammation, with a focus on recent findings on its mission as a damageassociated molecular pattern molecule and as a therapeutic target in inflammatory diseases. Recently generated HMGB1-specific inhibitors for treatment of inflammatory conditions are discussed.

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Section: Peptide P5779mentioning

confidence: 99%

“…In vitro Reduced HMGB1-induced TNF release from cultured human macrophages (48) Anti-HMGB1 mAb (m2G7)…”

Section: Puhnonary Hypertension In Ratsmentioning

confidence: 99%

Targeting Inflammation Driven by HMGB1

2020

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“…Recently, it was demonstrated that folic acid mimics the binding of P5779 at the intersection of TLR4 and MD-2. These folic acid-derived P5779 mimetics inhibit HMGB1-induced TNF release in human macrophages [189]. Recombinant human thrombomodulin (rTM) significantly decreases serum HMGB1 levels and improves systemic inflammatory response syndrome (SIRS) in patients with hematological malignancies [190].…”

Section: Small Peptides and Peptidomimeticsmentioning

confidence: 99%

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

et al. 2020

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High mobility group box 1 (HMGB1) is a nonhistone chromatin-associated protein that has been widely reported to play a pivotal role in the pathogenesis of hematopoietic malignancies. As a representative damage-associated molecular pattern (DAMP), HMGB1 normally exists inside cells but can be secreted into the extracellular environment through passive or active release. Extracellular HMGB1 binds with several different receptors and interactors to mediate the proliferation, differentiation, mobilization, and senescence of hematopoietic stem cells (HSCs). HMGB1 is also involved in the formation of the inflammatory bone marrow (BM) microenvironment by activating proinflammatory signaling pathways. Moreover, HMGB1-dependent autophagy induces chemotherapy resistance in leukemia and multiple myeloma. In this review, we systematically summarize the emerging roles of HMGB1 in carcinogenesis, progression, prognosis, and potential clinical applications in different hematopoietic malignancies. In summary, targeting the regulation of HMGB1 activity in HSCs and the BM microenvironment is highly beneficial in the diagnosis and treatment of various hematopoietic malignancies.

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“…The interaction of the TLR4 complex with HMGB1 can be blocked by the small molecule inhibitor P5779 95 . P5779 acts as an MD‐2 antagonist, blocking the binding of HMGB1 to MD‐2 as monitored by SPR and the subsequent HMGB1‐dependent release of TNF‐α in human macrophages 96 . The inhibition of TLR4 activation by P5779 was ligand‐specific as it did not inhibit LPS‐dependent TNF‐α release by human macrophages 95 …”

Section: Rage and Tlr4 Crosstalkmentioning

confidence: 99%

The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways

2020

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Although the innate immune receptor protein, Receptor for Advanced Glycation End products (RAGE), has been extensively studied, there has been renewed interest in RAGE for its potential role in sepsis, along with a host of other inflammatory diseases of chronic, noninfectious origin. In contrast to other innate immune receptors, for example, Toll-like receptors (TLRs), that recognize ligands derived from pathogenic organisms that are collectively known as "pathogen-associated molecular patterns" (PAMPs) or host-derived "damage-associated molecular patterns" (DAMPs), RAGE has been shown to recognize a broad collection of DAMPs exclusively. Historically, these DAMPs have been shown to be pro-inflammatory in nature. Early studies indicated that the adaptor molecule, MyD88, might be important for this change. More recent studies have explored further the mechanisms underlying this inflammatory change. Overall, the newer results have shown that there is extensive crosstalk between RAGE and TLRs. The three canonical RAGE ligands, Advanced Glycation End products (AGEs), HMGB1, and S100 proteins, have all been shown to activate both TLRs and RAGE to varying degrees in order to induce inflammation in in vitro models. As with any field that delves deeply into innate signaling, obstacles of reagent purity may be a cause of some of the discrepancies in the literature, and we have found that commercial antibodies that have been widely used exhibit a high degree of nonspecificity. Nonetheless, the weight of published evidence has led us to speculate that RAGE may be physically interacting with TLRs on the cell surface to elicit inflammation via MyD88-dependent signaling.

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Folic acid derived-P5779 mimetics regulate DAMP-mediated inflammation through disruption of HMGB1:TLR4:MD-2 axes

Cited by 18 publications

References 26 publications

Targeting Inflammation Driven by HMGB1

Targeting Inflammation Driven by HMGB1

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways

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