Worgall Tilla S
Columbia University Medical Center, New York City, New York, USA.
Curr Opin Clin Nutr Metab Care. 2017 Mar;20(2):99-103. doi: 10.1097/MCO.0000000000000349.
Genome-wide association studies identified ORMDL3, a protein of the endoplasmic reticulum, as a significant asthma risk factor. ORMDL3 is one of three ORMDL proteins that integrate multiple signals to maintain sphingolipid homeostasis. Studies that investigated potential mechanisms for how increased ORMDL3 might affect asthma are summarized.
Investigations focused on decreased sphingolipid synthesis and on the unfolded protein response because ORMDL3 had been implicated in both.Airway reactivity is increased in a genetic model with decreased de-novo sphingolipid synthesis and in wild-type mice treated with myriocin, a sphingolipid synthesis inhibitor. Inflammation, mucus production and airway smooth muscle hypertrophy are absent. ORMDL3 was not evaluated directly but results suggest that decreased sphingolipid synthesis is sufficient to induce airway hyperreactivity (AHR).Direct effects of ORMDL3 were investigated in allergic asthma models. Sensitization with ovalbumin, house dust mites and Alternaria alternata increase ORMDL3 mRNA. Universal overexpression of ORMDL3 decreases serum sphingolipids, increases inflammatory markers, airway remodeling and AHR in response to allergic stimuli. Addition of myriocin during sensitization drastically exacerbates house dust mites-induced AHR.ORMDL3 knockout mice are protected from developing A. alternata-induced AHR. The effect is specific to Alternaria and limited to smooth muscle contraction, as inflammation persists. ORMDL3 might have a critical role for smooth muscle contraction.Little is known about how the different ORMDL3 single nucleotide polymorphisms affect human blood and tissue sphingolipid profiles. One group measured total sphingoid levels and found no association with ORMDL3 single nucleotide polymorphisms in a general population. Others evaluated sphingolipid profiles in 7-8-year old children with mild asthma and found significantly higher C18 and C20 ceramides in those with persistence of asthma symptoms 3 years later, suggesting that sphingolipid profiles might predict asthma persistence.
Possible mechanisms how ORMDL3 affects asthma include inhibition of sphingolipid synthesis, synergistic effects with known allergens and a combination of both.
全基因组关联研究确定内质网蛋白ORMDL3是哮喘的一个重要风险因素。ORMDL3是整合多种信号以维持鞘脂稳态的三种ORMDL蛋白之一。本文总结了关于ORMDL3增加可能影响哮喘的潜在机制的研究。
研究集中在鞘脂合成减少和未折叠蛋白反应上，因为ORMDL3与这两者都有关联。在从头鞘脂合成减少的遗传模型以及用鞘脂合成抑制剂麦角硫因处理的野生型小鼠中，气道反应性增加。炎症、黏液分泌和气道平滑肌肥大均未出现。未直接评估ORMDL3，但结果表明鞘脂合成减少足以诱导气道高反应性（AHR）。
在变应性哮喘模型中研究了ORMDL3的直接作用。用卵清蛋白、屋尘螨和链格孢菌致敏会增加ORMDL3 mRNA。ORMDL3的普遍过表达会降低血清鞘脂水平，增加炎症标志物、气道重塑以及对变应性刺激的AHR。在致敏期间添加麦角硫因会显著加剧屋尘螨诱导的AHR。
ORMDL3基因敲除小鼠可免受链格孢菌诱导的AHR影响。这种作用对链格孢菌具有特异性，且仅限于平滑肌收缩，因为炎症持续存在。ORMDL3可能在平滑肌收缩中起关键作用。
关于不同的ORMDL3单核苷酸多态性如何影响人体血液和组织鞘脂谱知之甚少。一组测量了总鞘氨醇水平，发现在普通人群中与ORMDL3单核苷酸多态性无关联。其他研究评估了7 - 8岁轻度哮喘儿童的鞘脂谱，发现3年后仍有哮喘症状的儿童中C18和C20神经酰胺显著更高，这表明鞘脂谱可能预测哮喘的持续情况。
ORMDL3影响哮喘的可能机制包括抑制鞘脂合成、与已知变应原的协同作用以及两者的结合。
