FOXM1 促进变应原诱导的杯状细胞化生和肺部炎症。

FOXM1 promotes allergen-induced goblet cell metaplasia and pulmonary inflammation.

机构信息

Division of Pulmonary Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio, USA.

出版信息

Mol Cell Biol. 2013 Jan;33(2):371-86. doi: 10.1128/MCB.00934-12. Epub 2012 Nov 12.

Abstract

Chronic airway disorders, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are associated with persistent pulmonary inflammation and goblet cell metaplasia and contribute to significant morbidity and mortality worldwide. While the molecular pathogenesis of these disorders is actively studied, little is known regarding the transcriptional control of goblet cell differentiation and mucus hyperproduction. Herein, we demonstrated that pulmonary allergen sensitization induces expression of FOXM1 transcription factor in airway epithelial and inflammatory cells. Conditional deletion of the Foxm1 gene from either airway epithelium or myeloid inflammatory cells decreased goblet cell metaplasia, reduced lung inflammation, and decreased airway resistance in response to house dust mite allergen (HDM). FOXM1 induced goblet cell metaplasia and Muc5AC expression through the transcriptional activation of Spdef. FOXM1 deletion reduced expression of CCL11, CCL24, and the chemokine receptors CCR2 and CX3CR1, resulting in decreased recruitment of eosinophils and macrophages to the lung. Deletion of FOXM1 from dendritic cells impaired the uptake of HDM antigens and decreased cell surface expression of major histocompatibility complex II (MHC II) and costimulatory molecule CD86, decreasing production of Th2 cytokines by activated T cells. Finally, pharmacological inhibition of FOXM1 by ARF peptide prevented HDM-mediated pulmonary responses. FOXM1 regulates genes critical for allergen-induced lung inflammation and goblet cell metaplasia.

摘要

慢性气道疾病,包括慢性阻塞性肺疾病(COPD)、囊性纤维化和哮喘,与持续的肺部炎症和杯状细胞化生有关,并导致全球范围内的高发病率和死亡率。虽然这些疾病的分子发病机制正在积极研究,但对于杯状细胞分化和黏液高分泌的转录控制知之甚少。在此,我们证明肺部过敏原致敏诱导气道上皮细胞和炎症细胞中 FOXM1 转录因子的表达。Foxm1 基因在气道上皮细胞或髓样炎症细胞中的条件性缺失,可减少杯状细胞化生,减轻肺炎症,并降低对屋尘螨变应原(HDM)的气道阻力。FOXM1 通过 Spdef 的转录激活诱导杯状细胞化生和 Muc5AC 表达。FOXM1 缺失减少了 CCL11、CCL24 和趋化因子受体 CCR2 和 CX3CR1 的表达,导致嗜酸性粒细胞和巨噬细胞向肺部的募集减少。树突状细胞中 FOXM1 的缺失会损害 HDM 抗原的摄取,并降低主要组织相容性复合物 II(MHC II)和共刺激分子 CD86 的细胞表面表达,从而减少活化 T 细胞产生 Th2 细胞因子。最后,ARF 肽通过抑制 FOXM1 可防止 HDM 介导的肺部反应。FOXM1 调节与过敏原诱导的肺部炎症和杯状细胞化生相关的关键基因。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索