Seung-Hyun Kim1,2, Hae-Won Jung2, Minji Kim1,2, Ji-Young Moon2, Ga-Young Ban2,3, Su Jung Kim4, Hyun-Ju Yoo4, Hae-Sim Park2. 1. Translational Research Laboratory for Inflammatory Disease, Clinical Trial Center, Ajou University Medical Center, Suwon, South Korea. 2. Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea. 3. Department of Pulmonary, Allergy, and Critical Care Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine Institute for Life Sciences, Seoul, South Korea. 4. Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
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.
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.
Authors: Kathleen Lee-Sarwar; Sandra Dedrick; Babak Momeni; Rachel S Kelly; Robert S Zeiger; George T O'Connor; Megan T Sandel; Leonard B Bacharier; Avraham Beigelman; Nancy Laranjo; Diane R Gold; Jessica Lasky-Su; Augusto A Litonjua; Yang-Yu Liu; Scott T Weiss Journal: J Allergy Clin Immunol Date: 2022-02-20 Impact factor: 14.290