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sRAGE 通过阻断气道树突状细胞中的 HMGB1/RAGE 信号通路缓解中性粒细胞性哮喘。

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

机构信息

Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.

Department of Medical Genetics, The Third Military Medical University, Chongqing, China.

出版信息

Sci Rep. 2017 Oct 27;7(1):14268. doi: 10.1038/s41598-017-14667-4.

DOI:10.1038/s41598-017-14667-4
PMID:29079726
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5660212/
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.

摘要

晚期糖基化终产物受体（RAGE）在炎症反应中发挥作用。RAGE 的可溶性形式（sRAGE）作为诱饵，抑制 RAGE 与晚期糖基化终产物（如高迁移率族蛋白 B1（HMGB1））的相互作用。在之前的研究中，我们已经证明 HMGB1 通过调节树突状细胞（DC）的功能来指导 Th17 偏向。然而，sRAGE 阻断 HMGB1 在中性粒细胞性哮喘发展中的保护作用尚不清楚。在这里，我们表明，变应原挑战降低了中性粒细胞性哮喘小鼠模型中 sRAGE 的表达，与中性粒细胞计数和白细胞介素（IL）-17 产生密切相关。在致敏前通过气管内给予 sRAGE 阻断 HMGB1 信号，HMGB1 表达、中性粒细胞炎症和 Th17 型反应明显减少。sRAGE 通过抑制气道 CD11c 抗原呈递细胞中的 RAGE 和 IL-23 表达来实现抗哮喘作用。最后，我们表明 sRAGE 抑制了重组 HMGB1（rHMGB1）激活的树突状细胞（DC）体外诱导的 Th17 极化。rHMGB1 激活的 DC 的过继转移足以恢复气道炎症，而 rHMGB1 加 sRAGE 激活的 DC 的转移则显著减少中性粒细胞炎症。因此，sRAGE 通过阻断 DC 中的 HMGB1/RAGE 信号至少部分预防中性粒细胞性哮喘中的 Th17 介导的气道炎症。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/279a83a2a5d2/41598_2017_14667_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/ae7c4c52e655/41598_2017_14667_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/1b203163911b/41598_2017_14667_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/373e8bca1acf/41598_2017_14667_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/b08d5f8240c9/41598_2017_14667_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/c190e3b6b92e/41598_2017_14667_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/e8906dd18aa4/41598_2017_14667_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/563b24c669d5/41598_2017_14667_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/80bf05bfa5eb/41598_2017_14667_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/279a83a2a5d2/41598_2017_14667_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/ae7c4c52e655/41598_2017_14667_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/1b203163911b/41598_2017_14667_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/373e8bca1acf/41598_2017_14667_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/b08d5f8240c9/41598_2017_14667_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/c190e3b6b92e/41598_2017_14667_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/e8906dd18aa4/41598_2017_14667_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/563b24c669d5/41598_2017_14667_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/80bf05bfa5eb/41598_2017_14667_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0642/5660212/279a83a2a5d2/41598_2017_14667_Fig9_HTML.jpg

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