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.
Highlights
Allergic asthma is one of the most common airway diseases worldwide[1]
Using a mouse model of neutrophilic asthma induced by ovalbumin (OVA) plus lipopolysaccharide (LPS) sensitisation followed by three sequential daily OVA challenges (Fig. 1A), we investigated the functional relevance of Soluble RAGE (sRAGE) levels and allergic Th17 responses in the disease
Because High mobility group box 1 (HMGB1) has been identified as a crucial advanced glycation end product (AGE) that is involved in many inflammatory diseases, we considered that sRAGE may ameliorate airway inflammation via blockade of HMGB1 signalling
Summary
Allergic asthma is one of the most common airway diseases worldwide[1]. Asthma is generally considered as an airway inflammatory disease characterised by obstruction due to the stimulation of environmental antigens. Th17 cells are involved in the development of steroid-refractory and neutrophilic asthma[4], the underlying molecular mechanism responsible for the dysregulated immune responses mediated by Th17 cells still remains unclear. It is of great importance to perform further studies regarding the molecular mechanism of Th17 polarisation in neutrophilic asthma. Our previous study has demonstrated that HMGB1 directs Th17 skewing by regulating DC functions via IL-23 secretion, and blocking HMGB1 by an antibody may benefit attenuation of neutrophilic airway inflammation in asthma[19]. We evaluated whether sRAGE blocks HMBG1 signalling in DCs and subsequently contributes to alleviating Th17 polarisation in neutrophilic asthma, indicating that the HMBG1-RAGE axis might play a significant role in the development of neutrophilic asthma
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