Ceramide/sphingosine‐1‐phosphate imbalance is associated with distinct inflammatory phenotypes of uncontrolled asthma. Issue 8 (12th March 2020)

• Record Type: Journal Article
• Authors: Kim, Seung‐Hyun; Jung, Hae‐Won; Kim, Minji; Moon, Ji‐Young; Ban, Ga‐Young; Kim, Su Jung; Yoo, Hyun‐Ju; Park, Hae‐Sim
• Is Part Of: Allergy. Volume 75:Issue 8(2020)
• Page Start: 1991
• Page End: 2004
• Publication Date: 2020-03-12
• Subjects: asthma -- ceramide -- neutrophil -- platelet‐adherent eosinophil -- sphingosine‐1‐phosphate; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.14236
• Languages: English
• ISSNs: 0105-4538

Abstract

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. Abstract : Asthmatics patients with high level of CD66 + neutrophils have high C16:0 ceramide levels and enhanced ceramide‐mediated pro‐apoptotic signals (BID and JNK). Asthmatics patients with high level of platelet‐adherent eosinophils (CD61 + platelets/Siglec8 + eosinophils) have high S1P levels. The level of CD66 + neutrophils correlates with ROS production from neutrophils. The level of platelet‐adherent eosinophils is associated with asthma control symptom scores.