Sphingolipids, ORMDL3 and asthma: what is the evidence?

Abstract

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.