HMGB1 contributes to allergen-induced airway remodeling in a murine model of chronic asthma by modulating airway inflammation and activating lung fibroblasts

Hou, Chunmei; Kong, Jinliang; Ye, Liang; Huang, Hong; Wen, Huang; Zheng, Xiaowen; Wu, Lihong; Chen, Yiqiang

doi:10.1038/cmi.2014.60

Cited by 69 publications

(62 citation statements)

References 33 publications

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“…NRE, nonreducing end of ODSH sequences; RE, reducing end of ODSH sequences. ORIGINAL RESEARCH airway inflammation and remodeling in an ovalbumin-sensitized model of mouse asthma (38). These studies support the concept that HMGB1 is increased in inflammatory lung diseases and that inhibition of HMGB1 may prevent lung inflammation and injury.…”

Section: Discussionsupporting

confidence: 69%

2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity

Zheng

Kummarapurugu

Afosah

et al. 2017

Am J Respir Cell Mol Biol

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High mobility group box 1 (HMGB1) is an alarmin released from macrophages after infection or inflammation and is a biomarker of lung disease progression in patients with cystic fibrosis. We reported that 2-O, 3-O desulfated heparin (ODSH) inhibits the release of HMGB1 from murine macrophages triggered by neutrophil elastase both in vivo and in vitro. HMGB1 shuttles between the nucleus and the cytoplasm. When acetylated at lysine residues in the nuclear localization signal domains, HMGB1 is sequestered in the cytoplasm and is fated for secretion. In this study, we investigated the mechanism by which ODSH blocks HMGB1 secretion. We tested whether ODSH inhibits the activity of p300, a histone acetyltransferase that has been linked to HMGB1 acetylation and release. ODSH inhibited both neutrophil elastase and LPStriggered HMGB1 release from the murine macrophage cell line RAW264.7 in a concentration-dependent manner. Fluoresceinlabeled ODSH was taken up by RAW264.7 cells into the cytoplasm as well as the nucleus, suggesting an intracellular site of action of ODSH for blocking HMGB1 release. ODSH inhibited RAW264.7 cell nuclear extract, human macrophage nuclear extract, and recombinant p300 HAT activity in vitro, resulting in the failure to acetylate HMGB1. In silico molecular modeling predicted that of the numerous possible ODSH sequences, a small number preferentially recognizes a specific binding site on p300. Fluorescence binding studies showed that ODSH bound p300 tightly (dissociation constant z1 nM) in a highly cooperative manner. These results suggest that ODSH inhibited HMGB1 release, at least in part, by direct molecular inhibition of p300 HAT activity.Keywords: p300; heparin; high mobility group box 1 Clinical RelevanceWe report that a modified heparin, 2-O, 3-O desulfated heparin (ODSH), inhibits high mobility group box 1 release from macrophages via inhibition of a histone acetyltransferase, p300, required for acetylation. This is a novel mechanism by which ODSH blocks inflammation, and this finding supports the development of ODSH as an antiinflammatory therapy for cystic fibrosis.High mobility group box 1 (HMGB1) is found at high concentrations in the airways of patients with chronic inflammatory lung diseases. Increased airway HMGB1 is associated with bronchopulmonary dysplasia in preterm infants (1), severe asthma in children (2), and chronic obstructive pulmonary disease in adults (3, 4). HMGB1 is a biomarker for lung disease progression in patients with cystic fibrosis (CF) (4, 5). Furthermore, a polymorphism in the gene Ager, which encodes the HMGB1 receptor, receptor for advanced glycation end products (RAGE), results in increased RAGE expression

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Section: Discussionsupporting

confidence: 69%

2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity

Zheng

Kummarapurugu

Afosah

et al. 2017

Am J Respir Cell Mol Biol

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“…HMGB1 release has been shown after infection with various viruses, including RNA viruses (e.g., influenza virus H5N1, hepatitis C virus, West Nile virus, dengue virus, and HIV-1) (22,(49)(50)(51) and DNA viruses (e.g., herpes simplex virus type 2) (52), and HMGB1 has been implicated as an important mediator in the pathogenesis of these viral infections (53). Recent reports on asthma and COPD provide strong correlative evidence for HMGB1's involvement in lung inflammation (19,(54)(55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Respiratory Syncytial Virus Infection Triggers Epithelial HMGB1 Release as a Damage-Associated Molecular Pattern Promoting a Monocytic Inflammatory Response

Hosakote

Brasier

Casola

et al. 2016

J Virol

105

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Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infant and elderly populations worldwide. Currently, there is no efficacious vaccine or therapy available for RSV infection. The molecular mechanisms underlying RSV-induced acute airway disease and associated long-term consequences remain largely unknown; however, experimental evidence suggests that the lung inflammatory response plays a fundamental role in the outcome of RSV infection. High-mobility group box 1 (HMGB1) is a nuclear protein that triggers inflammation when released from activated immune or necrotic cells and drives the pathogenesis of various infectious agents. Although HMGB1 has been implicated in many inflammatory diseases, its role in RSV-induced airway inflammation has not been investigated. This study investigates the molecular mechanism of action of extracellularly released HMGB1 in airway epithelial cells (A549 and small airway epithelial cells) to establish its role in RSV infection. Immunofluorescence microscopy and Western blotting results showed that RSV infection of human airway epithelial cells induced a significant release of HMGB1 as a result of translocation of HMGB1 from the cell nuclei to the cytoplasm and subsequent release into the extracellular space. Treating RSV-infected A549 cells with antioxidants significantly inhibited RSV-induced HMGB1 extracellular release. Studies using recombinant HMGB1 triggered immune responses by activating primary human monocytes. Finally, HMGB1 released by airway epithelial cells due to RSV infection appears to function as a paracrine factor priming epithelial cells and monocytes to inflammatory stimuli in the airways. IMPORTANCERSV is a major cause of serious lower respiratory tract infections in young children and causes severe respiratory morbidity and mortality in the elderly. In addition, to date there is no effective treatment or vaccine available for RSV infection. The mechanisms responsible for RSV-induced acute airway disease and associated long-term consequences remain largely unknown. The oxidative stress response in the airways plays a major role in the pathogenesis of RSV. HMGB1 is a ubiquitous redox-sensitive multifunctional protein that serves as both a DNA regulatory protein and an extracellular cytokine signaling molecule that promotes airway inflammation as a damage-associated molecular pattern. This study investigated the mechanism of action of HMGB1 in RSV infection with the aim of identifying new inflammatory pathways at the molecular level that may be amenable to therapeutic interventions. R espiratory syncytial virus (RSV) is a ubiquitous, negativesense, enveloped, single-stranded RNA virus that frequently causes upper and lower respiratory tract infections in infants, young children, the elderly, and immunocompromised individuals. Epidemiological evidence indicates that severe pulmonary disease caused by RSV infection in infancy is associated with recurrent wheezing and the development of asthma later in childhood. No ...

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“…It has been shown to lead to calcium mobilization and increases the excitability of primary DRG neurons , driving pain hypersensitivity . HMGB1‐TLR4 interplay drives clinical conditions such as sepsis, arthritis , cancer and potentially asthma (reviewed by Imbalzano et al . ).…”

Section: Endogenous Triggersmentioning

confidence: 99%

Profiling of how nociceptor neurons detect danger – new and old foes

et al. 2019

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The host evolves redundant mechanisms to preserve physiological processing and homeostasis. These functions range from sensing internal and external threats, creating a memory of the insult and generating reflexes, which aim to resolve inflammation. Impairment in such functioning leads to chronic inflammatory diseases. By interacting through a common language of ligands and receptors, the immune and sensory nervous systems work in concert to accomplish such protective functions. Whilst this bidirectional communication helps to protect from danger, it can contribute to disease pathophysiology. Thus, the somatosensory nervous system is anatomically positioned within primary and secondary lymphoid tissues and mucosa to modulate immunity directly. Upstream of this interplay, neurons detect danger, which prompts the release of neuropeptides initiating (i) defensive reflexes (ranging from withdrawal response to coughing) and (ii) chemotaxis, adhesion and local infiltration of immune cells. The resulting outcome of such neuro‐immune interplay is still ill‐defined, but consensual findings start to emerge and support neuropeptides not only as blockers of TH1‐mediated immunity but also as drivers of TH2 immune responses. However, the modalities detected by nociceptors revealed broader than mechanical pressure and temperature sensing and include signals as various as cytokines and pathogens to immunoglobulins and even microRNAs. Along these lines, we aggregated various dorsal root ganglion sensory neuron expression profiling datasets supporting such wide‐ranging sensing capabilities to help identifying new danger detection modalities of these cells. Thus, revealing unexpected aspects of nociceptor neuron biology might prompt the identification of novel drivers of immunity, means to resolve inflammation and strategies to safeguard homeostasis.

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HMGB1 contributes to allergen-induced airway remodeling in a murine model of chronic asthma by modulating airway inflammation and activating lung fibroblasts

Cited by 69 publications

References 33 publications

2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity

2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity

Respiratory Syncytial Virus Infection Triggers Epithelial HMGB1 Release as a Damage-Associated Molecular Pattern Promoting a Monocytic Inflammatory Response

Profiling of how nociceptor neurons detect danger – new and old foes

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