Gartner J G, Durston M M, Booth S A, Ellison C A
Department of Pathology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Scand J Immunol. 2017 Nov;86(5):368-376. doi: 10.1111/sji.12597. Epub 2017 Sep 29.
Acute GVHD (aGVHD) is driven by interactions between the allogenic T cell response, inflammation, tissue injury and microbial products that enter the circulation when protective barriers such as the intestinal epithelium become compromised. Mice with aGVHD become hypersensitive to LPS, secreting large quantities of inflammatory mediators that exacerbate tissue injury. We hypothesized that microRNA (miR) modulators could be used in vivo to mitigate LPS hypersensitivity, altering the course of aGVHD. Using the C57BL/6 → (C57BL/6 × DBA/2)F -hybrid model of aGVHD, we measured intestinal permeability over time and used a qPCR array to detect concomitant changes in the expression levels of certain microRNAs (miRs) in the intestine. Large increases in permeability were seen on day 15, when endotoxemia becomes detectable and GVHD-associated histopathological lesions develop. Amongst the miRs with altered expression levels were some that regulate sensitivity to endotoxin. We chose to focus on miR-146a and treated recipient mice systemically with a miR-146a mimic early in the GVH reaction. This led to a reduction in the burst of IFNγ that likely plays a priming role in the mechanism underlying heightened sensitivity to endotoxin. LPS-induced TNFα release and GVHD-associated weight loss were also diminished and survival was prolonged. In summary, systemic treatment with a miR-146a mimic dampens the heightened sensitivity to LPS that occurs concomitantly with increased intestinal permeability and provides partial protection from the progression of acute GVHD.
急性移植物抗宿主病（aGVHD）是由同种异体T细胞反应、炎症、组织损伤以及当肠道上皮等保护屏障受损时进入循环的微生物产物之间的相互作用所驱动的。患有aGVHD的小鼠对脂多糖（LPS）变得高度敏感，分泌大量加剧组织损伤的炎症介质。我们假设微小RNA（miR）调节剂可在体内用于减轻LPS超敏反应，改变aGVHD的病程。使用aGVHD的C57BL/6→（C57BL/6×DBA/2）F1杂交模型，我们随时间测量肠道通透性，并使用定量PCR阵列检测肠道中某些微小RNA（miRs）表达水平的伴随变化。在第15天观察到通透性大幅增加，此时可检测到内毒素血症且出现与GVHD相关的组织病理学损伤。在表达水平发生改变的miRs中，有一些调节对内毒素的敏感性。我们选择聚焦于miR-146a，并在GVH反应早期对受体小鼠进行全身性miR-146a模拟物治疗。这导致IFNγ的爆发减少，而IFNγ可能在对内毒素高度敏感的潜在机制中起引发作用。LPS诱导的TNFα释放和与GVHD相关的体重减轻也有所减轻，并且生存期延长。总之，全身性miR-146a模拟物治疗可减轻与肠道通透性增加同时出现的对LPS的高度敏感性，并为急性GVHD的进展提供部分保护。
