Airway reactivity and sphingolipids—implications for childhood asthma

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.

Novel eosinophilic gene expression networks associated with IgE in two distinct asthma populations

“…CCL23 is an eosinophilic chemokine, that has been identified as a possible biomarker for anti-IL13 targeted therapies (49, 50). Several of these are enzymes expressed within eosinophils, such as CLC, IDO1, SMPD3 , and SPNS3 , and the latter two are both involved in the sphingolipid pathways, known to mediate airway hyperresponsiveness and mast cell activation (51, 52). Another gene CAMK1 has been implicated as an asthma control gene(20), but has not been identified previously with IgE or an allergy-related phenotype among individuals diagnosed with asthma.…”

“…Other genes from our eosinophil-related gene sets have known associations with allergic asthma and may also have therapeutic or diagnostic potential, including CCL23, CLC, CEBPE, CAMK1, IDO1, SIGLEC8, SMPD3 and SPNS3. [44][45][46][47][48][49][50][51] Potential therapeutic targets include cell surface receptors, such as Siglec8, an inhibitory receptor on eosinophils with polymorphisms associated with asthma. [45][46][47] CCL23 is an eosinophilic chemokine that has been identified as a possible biomarker for anti-IL13-targeted therapies.…”

“…48,49 Several of these are enzymes expressed within eosinophils, such as CLC, IDO1, SMPD3 and SPNS3, and the latter two are both involved in the sphingolipid pathways, known to mediate airway hyperresponsiveness and mast cell activation. 50,51 Another gene CAMK1 has been implicated as an asthma control gene, 20 but has not been identified previously with IgE or an allergy-related phenotype among individuals diagnosed with asthma. Of the calmodulin-dependent kinases, CAMK2 and CAMK4 have been implicated in bronchoconstriction and smooth muscle proliferation, 52,53 suggesting that CAMK1 may also play a role in asthma pathogenesis.…”

Sphingolipid metabolism potential in fecal microbiome and bronchiolitis in infants: a case–control study

“…Sphingolipids are a class of complex lipids containing a backbone of sphingoid bases. These lipids have long been known as structural components of human cell membranes and as a component of surfactant, but have more recently emerged as signaling molecules that modulate the host immune response and contribute to the pathogenesis of respiratory diseases, such as bronchiolitis, pneumonia, and asthma [ 7 , 22 ]. While sphingolipids production is ubiquitous in eukaryotes, it is also produced by several bacteria genera such as Bacteroides , Prevotella , and Porphyromonas [ 12 ].…”

Why is Chromosome 17q21 linked to Asthma?

“…ORMDL3 activates ATF-6α pathway during ER unfolded response and induces sarco/endoplasmic reticulum Ca 2+ ATPases pump (SERCA2b) to regulate ER-mediated Ca 2+ signaling and cellular stress response [12,13]. ORMDL3 acts as a mediator of sphingolipid homeostasis [14,15] and can also regulate eosinophil trafficking, recruitment and degranulation [16]. Studies of mice generated to express increased levels of human ORMDL3 have also demonstrated that in vivo ORMDL3 activates ATF6α (but not Ire1 or PERK), and that this is associated with increased expression of SERCA2b.…”