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Host engulfment pathway controls inflammation in Inflammatory Bowel Disease.

宿主吞噬通路控制炎症性肠病的炎症。

  • 影响因子:4.22
  • DOI:10.1111/febs.15236
  • 作者列表:"Sayed IM","Suarez K","Lim E","Singh S","Pereira M","Ibeawuchi SR","Katkar G","Dunkel Y","Mittal Y","Chattopadhyay R","Guma M","Boland BS","Dulai PS","Sandborn WJ","Ghosh P","Das S
  • 发表时间:2020-01-30
Abstract

:Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.

摘要

: 慢性疾病,包括炎症性肠病 (IBD) 迫切需要新的生物标志物,作为很大一部分患者,对当前的药物治疗没有反应。炎症是这些疾病的常见因素,肠道中的微生物感知是启动炎症的关键。我们已经确定 ELMO1 (吞噬和细胞运动蛋白-1) 是上皮和吞噬细胞中开启炎症信号的微生物传感器。使用基于干细胞的 “菜中肠” 共培养模型,我们研究了 IBD 背景下微生物、上皮和单核细胞之间的相互作用。为了模拟体内细胞生理学,从 WT 和 ELMO1-/-小鼠和 IBD 患者的结肠活检中分离出的类器官生成了类肠道来源的单层 (EDMs)。EDMs 感染 IBD 相关微生物以监测炎症反应。ELMO1-depleted EDMs 显示细菌内化显著减少,促炎细胞因子产生和单核细胞募集减少。ELMO1 在 IBD 患者结肠上皮和固有层内炎症浸润中的表达升高,其中高表达与促炎细胞因子的表达升高呈正相关, MCP-1 和 TNF-α。MCP-1 从上皮细胞释放并招募单核细胞到炎症部位。一旦招募,单核细胞需要 ELMO1 吞噬细菌并繁殖强大的 TNF-α 风暴。这些发现强调,上皮细胞 ELMO1 → MCP-1 轴失调可以作为 IBD 和其他炎症性疾病诊断的早期生物标志物。

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相关文献
影响因子:4.22
发表时间:2020-01-30
来源期刊:The FEBS journal
DOI:10.1111/febs.15236
作者列表:["Sayed IM","Suarez K","Lim E","Singh S","Pereira M","Ibeawuchi SR","Katkar G","Dunkel Y","Mittal Y","Chattopadhyay R","Guma M","Boland BS","Dulai PS","Sandborn WJ","Ghosh P","Das S"]

METHODS::Chronic diseases, including inflammatory bowel disease (IBD) urgently need new biomarkers as a significant proportion of patients, do not respond to current medications. Inflammation is a common factor in these diseases and microbial sensing in the intestinal tract is critical to initiate the inflammation. We have identified ELMO1 (Engulfment and Cell Motility Protein-1) as a microbial sensor in epithelial and phagocytic cells that turns on inflammatory signals. Using a stem-cell-based "gut-in-a-dish" coculture model, we studied the interactions between microbes, epithelium and monocytes in the context of IBD. To mimic the in-vivo cell physiology, enteroid-derived monolayers (EDMs) were generated from the organoids isolated from WT and ELMO1-/- mice and colonic biopsies of IBD patients. The EDMs were infected with the IBD-associated microbes to monitor the inflammatory responses. ELMO1-depleted EDMs displayed a significant reduction in bacterial internalization, a decrease in pro-inflammatory cytokine productions and monocyte recruitment. The expression of ELMO1 is elevated in the colonic epithelium and in the inflammatory infiltrates within the lamina propria of IBD patients where the higher expression is positively correlated with the elevated expression of pro-inflammatory cytokines, MCP-1 and TNF-α. MCP-1 is released from the epithelium and recruits monocytes to the site of inflammation. Once recruited, monocytes require ELMO1 to engulf the bacteria and propagate a robust TNF-α storm. These findings highlight that the dysregulated epithelial ELMO1→MCP-1 axis can serve as an early biomarker in the diagnostics of IBD and other inflammatory disorders.

影响因子:3.72
发表时间:2020-01-21
DOI:10.1093/ibd/izz323
作者列表:["Prathapan KM","Ramos Rivers C","Anderson A","Koutroumpakis F","Koutroubakis IE","Babichenko D","Tan X","Tang G","Schwartz M","Proksell S","Johnston E","Hashash JG","Dunn M","Wilson A","Barrie A","Harrison J","Hartman D","Kim SC","Binion DG"]

METHODS:BACKGROUND:Peripheral blood eosinophilia (PBE) is a biomarker of an aggressive multiyear natural history in adults with inflammatory bowel diseases (IBDs). Additionally, PBE at diagnosis is associated with higher disease activity in pediatric-onset IBD. We sought to determine if PBE can function as a biomarker of long-term disease severity in pediatric-onset IBD patients who are followed into adulthood. METHODS:We analyzed a consented, prospective, natural history IBD registry at an adult tertiary center from 2009 to 2018. Prevalence of PBE was evaluated in both pediatric- and adult-onset IBD patients. Demographics, clinical characteristics, and health care utilization data were compared in patients with and without PBE. RESULTS:Among 2800 adult IBD patients, 23.4% had pediatric-onset disease. PBE was found in 34% of the pediatric-onset patients compared with 26.8% of the adult-onset IBD patients (P < 0.001). In the pediatric-onset IBD cohort, PBE was associated with higher rates of allergies (P < 0.0001), but not of asthma, allergic rhinitis, or primary sclerosing cholangitis. In the adult IBD patients with pediatric-onset disease, PBE was associated with higher rates of C-reactive protein elevation (P < 0.0001), erythrocyte sedimentation rate elevation (P < 0.0001), higher health care utilization, and higher average health care charges per year (P < 0.00001). CONCLUSIONS:Peripheral blood eosinophilia was more prevalent in adult IBD patients with pediatric-onset compared with adult-onset disease. Among all IBD patients with long-term follow-up, PBE defined a subgroup with more severe illness. These data suggest that PBE may be a biomarker for a high-risk subgroup with high cost trajectory and long-term severity in pediatric-onset IBD that persists into adulthood.

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影响因子:3.72
发表时间:2020-01-21
DOI:10.1093/ibd/izz331
作者列表:["Ronchetti S","Gentili M","Ricci E","Migliorati G","Riccardi C"]

METHODS::Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.

关键词: GILZ IBD 自身免疫 炎症
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