Dataset Information

SRAGE alleviates neutrophilic asthma by blocking HMGB1/RAGE signalling in airway dendritic cells.

ABSTRACT: Receptor for advanced glycation end products (RAGE) plays a role in inflammatory reactions. The soluble form of RAGE (sRAGE) acts as a decoy to inhibit interactions of RAGE with advanced glycation end products such as High mobility group box 1 (HMGB1). We have demonstrated that HMGB1 directs Th17 skewing by regulating dendritic cell (DC) functions in a previous study. However, the protective effects of HMGB1 blockade with sRAGE in the development of neutrophilic asthma remain unclear. Here, we showed that allergen challenge decreased expression of sRAGE in a murine model of neutrophilic asthma, correlating well with neutrophil counts and interleukin (IL)-17 production. When HMGB1 signalling was blocked by intratracheal administration of sRAGE before sensitisation, HMGB1 expression, neutrophilic inflammation, and Th17-type responses were reduced significantly. Anti-asthma effects of sRAGE were achieved by inhibition of RAGE and IL-23 expression in airway CD11c⁺ antigen-presenting cells. Finally, we showed that sRAGE inhibited Th17 polarisation induced by recombinant HMGB1 (rHMGB1)-activated dendritic cells (DCs) in vitro. Adoptive transfer of rHMGB1-activated DCs was sufficient to restore airway inflammation, whereas transfer of rHMGB1 plus sRAGE-activated DCs significantly reduced neutrophilic inflammation. Thus, sRAGE prevents Th17-mediated airway inflammation in neutrophilic asthma at least partly by blocking HMGB1/RAGE signalling in DCs.

SUBMITTER: Zhang F

PROVIDER: S-EPMC5660212 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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sRAGE alleviates neutrophilic asthma by blocking HMGB1/RAGE signalling in airway dendritic cells.

Zhang Fang F Su Xin X Huang Gang G Xin Xiao-Feng XF Cao E-Hong EH Shi Yi Y Song Yong Y

Scientific reports 20171027 1

Receptor for advanced glycation end products (RAGE) plays a role in inflammatory reactions. The soluble form of RAGE (sRAGE) acts as a decoy to inhibit interactions of RAGE with advanced glycation end products such as High mobility group box 1 (HMGB1). We have demonstrated that HMGB1 directs Th17 skewing by regulating dendritic cell (DC) functions in a previous study. However, the protective effects of HMGB1 blockade with sRAGE in the development of neutrophilic asthma remain unclear. Here, we s ...[more]

PMID: 29079726

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Project description:BackgroundMolecular microbiological analysis of airway samples in asthma has demonstrated an altered microbiome in comparison to healthy controls. Such changes may have relevance to treatment-resistant severe asthma, particularly those with neutrophilic airway inflammation, as bacteria might be anticipated to activate the innate immune response, a process that is poorly steroid responsive. An understanding of the relationship between airway bacterial presence and dominance in severe asthma may help direct alternative treatment approaches.ObjectiveWe aimed to use a culture independent analysis strategy to describe the presence, dominance and abundance of bacterial taxa in induced sputum from treatment resistant severe asthmatics and correlate findings with clinical characteristics and airway inflammatory markers.MethodsInduced sputum was obtained from 28 stable treatment-resistant severe asthmatics. The samples were divided for supernatant IL-8 measurement, cytospin preparation for differential cell count and Terminal Restriction Fragment Length Polymorphism (T-RFLP) profiling for bacterial community analysis.ResultsIn 17/28 patients, the dominant species within the airway bacterial community was Moraxella catarrhalis or a member of the Haemophilus or Streptococcus genera. Colonisation with these species was associated with longer asthma disease duration (mean (SD) 31.8 years (16.7) vs 15.6 years (8.0), p = 0.008), worse post-bronchodilator percent predicted FEV1 (68.0% (24.0) vs 85.5% (19.7), p = 0.025) and higher sputum neutrophil differential cell counts (median (IQR) 80% (67-83) vs 43% (29-67), p = 0.001). Total abundance of these organisms significantly and positively correlated with sputum IL-8 concentration and neutrophil count.ConclusionsAirway colonisation with potentially pathogenic micro-organisms in asthma is associated with more severe airways obstruction and neutrophilic airway inflammation. This altered colonisation may have a role in the development of an asthma phenotype that responds less well to current asthma therapies.

Dataset Information

SRAGE alleviates neutrophilic asthma by blocking HMGB1/RAGE signalling in airway dendritic cells.

Publications

sRAGE alleviates neutrophilic asthma by blocking HMGB1/RAGE signalling in airway dendritic cells.

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