Ceramide in apoptosis and oxidative stress in allergic inflammation and asthma

Background Nothing is known about the mechanisms by which increased ceramide levels in the lung contribute to allergic responses and asthma severity. Objective We sought to investigate the functional role of ceramide in mouse models of allergic airway disease that recapitulate the cardinal clinical features of human allergic asthma. Methods Allergic airway disease was induced in mice by repeated intranasal administration of house dust mite or the fungal allergen Alternaria alternata. Processes that can be regulated by ceramide and are important for severity of allergic asthma were correlated with ceramide levels measured by mass spectrometry. Results Both allergens induced massive pulmonary apoptosis and also significantly increased reactive oxygen species in the lung. Prevention of increases in lung ceramide levels mitigated allergen-induced apoptosis, reactive oxygen species, and neutrophil infiltration. In contrast, dietary supplementation of the antioxidant α-tocopherol decreased reactive oxygen species but had no significant effects on elevation of ceramide level or apoptosis, indicating that the increases in lung ceramide levels in allergen-challenged mice are not mediated by oxidative stress. Moreover, specific ceramide species were altered in bronchoalveolar lavage fluid from patients with severe asthma compared with in bronchoalveolar lavage fluid from individuals without asthma. Conclusion Our data suggest that elevation of ceramide level after allergen challenge contributes to the apoptosis, reactive oxygen species generation, and neutrophilic infiltrate that characterize the severe asthmatic phenotype. Ceramide might be the trigger of formation of Creola bodies found in the sputum of patients with severe asthma and could be a biomarker to optimize diagnosis and to monitor and improve clinical outcomes in this disease

Anti-Tumor Functions of Sphingosine Kinase 1 and Sphingosine Kinase 2 in Breast Cancer Development

Bioactive sphingolipid metabolite sphingosine-1‐phosphate (S1P) circulating levels have been implicated in breast cancer (BC) progression. BCs usually respond to 17β-Estradiol (E2) through canonical receptor ERα66 for genomic effects, however, E2 also triggers rapid, non-genomic responses. E2 has been shown to activate sphingosine kinase 1 (SphK1), increasing S1P for S1P receptors signaling important for BC. The E2 receptor activating SphK1 has not been identified. We demonstrate triple negative BC cells, expressing only novel ERα splice variant ERα36, E2-induced SphK1 activation for S1P secretion. Tamoxifen, first-line BC endocrine therapy, an ERα66 antagonist but ERα36 agonist, activates SphK1 and increases S1P secretion in tamoxifen resistant BCs. Furthermore, tamoxifen resistance correlates with increased SphK1 and ERα36 expression in patients. Therefore, targeting ERα36 and SphK1 axis may be a therapeutic option to circumvent endocrine resistance and improve patient outcome. In contrast, surprisingly, deletion or inhibition of the other isoenzyme that produces S1P, sphingosine kinase 2 (SphK2), shown to greatly increases circulating levels of S1P, markedly suppressed syngeneic triple-negative BC growth and pulmonary metastasis. In these lungs, immunosuppressive PMN-MDSCs and Tregs decreased and immunostimulant T effector, NK and M1 macrophages increased, creating a hostile microenvironment. Intriguingly, SphK2 inhibition or deletion increased lung ceramide and tumor suppressor p53 expression to decrease the genetic transformation of normal fibroblast to cancer-associated fibroblasts (CAF), restraining the CAF tumor-promoting secretome and creating an active anti-tumor microenvironment. This work highlights SphK2/p53 axis in stromal fibroblasts and suggests targeting SphK2 may pave way for development of novel targeted immunotherapeutics to boost anti-cancer immunity