Abstract
Asthma is a clinically heterogeneous disorder, whose onset and progression results from a complex interplay between genetic susceptibility, allergens, and viral triggers. Sphingolipids and altered sphingolipid metabolism have emerged as potential key contributors to the pathogenesis of asthma. Orosomucoid-like 3 gene (ORMDL3) and the asthma susceptibility locus 17q21 have been strongly and reproducibly linked to childhood asthma, but how this gene is functionally linked to asthma is incompletely understood. ORMDL proteins play an integral role in sphingolipid homeostasis and synthesis, and asthma-associated ORMDL3 polymorphisms have been associated with early viral respiratory infections and increased risk of asthma. ORMDL proteins act as inhibitors of serine palmitoyl-CoA transferase (SPT), the rate-limiting enzyme for de novo sphingolipid synthesis, and decreased sphingolipid synthesis through SPT increases airway hyperreactivity, which is independent of allergy or inflammation. In allergic models of asthma, the sphingolipid mediators sphingosine-1-phosphate (S1P) and ceramide have been shown to be important signaling molecules for airway hyperreactivity, mast cell activation, and inflammation. This review will highlight how sphingolipids and altered sphingolipid metabolism may contribute towards the underlying mechanisms of childhood asthma.
Highlights
Asthma is a chronic airway disease characterized by reversible airway obstruction, chronic inflammation, mucous production, and airway hyperreactivity
Given that the asthma-associated orosomucoid-like 3 gene (ORMDL3) polymorphisms lead to increased expression of ORMDL3 [38], it has been suggested that asthma-associated single nucleotide polymorphism (SNP) negatively regulate serine palmitoylCoA transferase (SPT) resulting in inhibited de novo sphingolipid synthesis [64]
Robust overexpression of ORMDL3 resulted in overall increased ceramide levels [22, 62] suggesting a possible contribution of the recycling/salvage sphingolipid synthesis pathways [22] and indicating that relative cellular concentrations of SPT and ORMDL are important in the regulation of de novo sphingolipid synthesis by ORMDL expression [62]
Summary
Asthma is a chronic airway disease characterized by reversible airway obstruction, chronic inflammation, mucous production, and airway hyperreactivity. While the functions of ORMDL3 are incompletely understood, it is known to be involved in sphingolipid metabolism and de novo sphingolipid synthesis [6], suggesting altered sphingolipid metabolism as a contributing factor in asthma. This suggested that variants at this asthma susceptibility locus may regulate ORMDL3 expression, having been confirmed in rhinovirus-infected blood cells [43].
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