Ceramide/sphingosine‐1‐phosphate imbalance is associated with distinct inflammatory phenotypes of uncontrolled asthma

Abstract

Background: Asthma is associated with inflammatory dysregulation, but the underlying metabolic signatures are unclear. This study aimed to classify asthma inflammatory phenotypes based on cellular and metabolic features. Methods: To determine cellular and metabolic profiles, we assessed inflammatory cell markers using flow cytometry, sphingolipid (SL) metabolites using LC-MS/MS, and serum cytokines using ELISA. Targeted gene polymorphisms were determined to identify genetic predispositions related to the asthma inflammatory phenotype. Results: In total, 137 patients with asthma and 20 healthy controls (HCs) were enrolled. Distinct cellular and metabolic profiles were found between them; patients with asthma showed increased expressions of inflammatory cell markers and higher levels of SL metabolites compared to HCs (P < .05 for all). Cellular markers (CD66 + neutrophils, platelet-adherent eosinophils) and SL metabolic markers (C16:0 and C24:0 ceramides) for uncontrolled asthma were also identified; higher levels were observed in uncontrolled asthma compared to controlled asthma (P < .05 for all). Asthmatics patients with higher levels of CD66 + neutrophils had lower FEV1(%), higher ACQ (but lower AQLO) scores, and higher sphingosine and C16:0 ceramide levels compared to those with low levels of CD66 + neutrophils. Asthmatics patients with higher levels of platelet-adherent eosinophils had higher S1P levels compared to those with lower levels of platelet-adherent eosinophils. Patients carrying TT genotype of ORMDL3 had more CD66 + neutrophils; those with AG/ GG genotypes of SGMS1 exhibited higher platelet-adherent eosinophils. Conclusion: Patients with uncontrolled asthma possess distinct inflammatory phenotypes including increased CD66 + neutrophils and platelet-adherent eosinophils, with an imbalanced ceramide/S1P rheostat, potentially involving ORMDL3 and SGMS1 gene polymorphisms. Ceramide/S1P synthesis could be targeted to control airway inflammation.

Advances and recent developments in asthma in 2020

“…81 The increased serum IL- 33 The DP2 receptor is an essential regulator in allergic asthma because it can be activated by both allergic and nonallergic stimuli. 88 The activation of the DP2 receptor pathway increases both 89 Kim et al 90 showed that the ceramide/sphingosine-1-phosphate ratio can discriminate between two different asthma endotypes. however, it did not have an impact on the differentiating of other CD4+ T-cell subsets.…”

Increased expression of serine palmitoyl transferase and ORMDL3 polymorphism are associated with eosinophilic inflammation and airflow limitation in aspirin-exacerbated respiratory disease

“…Ceramides in bronchoalveolar lavage fluid have been reported to be associated with airway inflammation and hyperreactivity in mouse models of house dust mite-induced asthma and neutrophil elastase [14,28]. A recent study demonstrated that the serum levels of ceramides were higher in asthmatic patients than in healthy controls and in asthmatic patients in an uncontrolled than in a controlled state [30]. Untargeted and targeted metabolomics study that aimed to determine different metabotypes according to asthma severity revealed that the serum levels of S1P, sphingosine and ceramides were high in severe asthmatics [31].…”

“…Despite accumulating evidence for the recycling synthetic pathway of sphingolipids [13,14,16,28,30,31], there are scanty data on the role of the de novo synthetic pathway of sphingolipids in asthma pathogenesis [29]. The pathogenic role of the de novo synthetic pathway has been suggested from the GWAS studies showing that ORMDL and CerS2 were significantly associated with the risk of asthma [21,22,32,33].…”

Ceramide induces MMP-9 expression through JAK2/STAT3 pathway in airway epithelium

“…Ceramide is significantly increased in the lungs and serum of patients with asthma and COPD [ 14 , 15 ]. Ceramide is also associated with the phenotypes of asthma and COPD, and may contribute to exacerbation and poor disease control by worsening airway inflammation [ 16 , 17 ]. Studies by Oyeniran et al showed that intratracheal delivery of ceramide in mice promoted pulmonary inflammation and tissue remodeling, and caused airway flow obstruction [ 18 ].…”