当前位置: X-MOL 学术Mucosal Immunol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Phosphatidylinositol 3-kinase p110δ drives intestinal fibrosis in SHIP deficiency.
Mucosal Immunology ( IF 8 ) Pub Date : 2019-07-29 , DOI: 10.1038/s41385-019-0191-z
Young Lo 1 , Jean Philippe Sauve 1 , Susan C Menzies 1 , Theodore S Steiner 2 , Laura M Sly 1
Affiliation  

Crohn's disease is an immune-mediated disease characterized by inflammation along the gastrointestinal tract. Fibrosis requiring surgery occurs in one-third of people with Crohn's disease but there are no treatments for intestinal fibrosis. Mice deficient in the SH2 domain-containing inositolpolyphosphate 5'-phosphatase (SHIP), a negative regulator of phosphatidylinositol 3-kinase (PI3K) develop spontaneous Crohn's disease-like intestinal inflammation and arginase I (argI)-dependent fibrosis. ArgI is up-regulated in SHIP deficiency by PI3Kp110δ activity. Thus, we hypothesized that SHIP-deficient mice develop fibrosis due to increased PI3Kp110δ activity. In SHIP-deficient mice, genetic ablation or pharmacological inhibition of PI3Kp110δ activity reduced intestinal fibrosis, including muscle thickening, accumulation of vimentin+ mesenchymal cells, and collagen deposition. PI3Kp110δ deficiency or inhibition also reduced ileal inflammation in SHIP-deficient mice suggesting that PI3Kp110δ may contribute to inflammation. Targeting PI3Kp110δ activity may be an effective strategy to reduce intestinal fibrosis, and may be particularly effective in the subset of people with Crohn's disease, who have low SHIP activity.

中文翻译:

磷脂酰肌醇 3-激酶 p110δ 驱动 SHIP 缺陷的肠道纤维化。

克罗恩病是一种免疫介导的疾病,其特征是沿着胃肠道发炎。三分之一的克罗恩病患者出现需要手术的纤维化,但目前还没有治疗肠道纤维化的方法。缺乏含肌醇多磷酸 5'-磷酸酶 (SHIP) 的 SH2 结构域(磷脂酰肌醇 3-激酶 (PI3K) 的负调节因子)的小鼠会出现自发性克罗恩病样肠道炎症和精氨酸酶 I (argI) 依赖性纤维化。ArgI 通过 PI3Kp110δ 活性在 SHIP 缺陷中上调。因此,我们假设 SHIP 缺陷小鼠由于 PI3Kp110δ 活性增加而发生纤维化。在 SHIP 缺陷小鼠中,PI3Kp110δ 活性的基因消融或药理学抑制减少了肠道纤维化,包括肌肉增厚,波形蛋白+间充质细胞的积累和胶原沉积。PI3Kp110δ 缺乏或抑制也减少了 SHIP 缺陷小鼠的回肠炎症,表明 PI3Kp110δ 可能导致炎症。靶向 PI3Kp110δ 活性可能是减少肠道纤维化的有效策略,并且可能对 SHIP 活性较低的克罗恩病患者特别有效。
更新日期:2019-11-18
down
wechat
bug