Inhibition of acid sphingomyelinase in bronchial asthma – deciphering the T cell mediated effects

• Applicant: Privatdozent Dr. Christian Martin, since 4/2024
• Subject Area: Pediatric and Adolescent Medicine ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 510227901

Bronchial asthma is a chronic inflammatory disease of the lung with rising prevalence in childhood, but also in adults. Clinical characteristics of this TH2-mediated disease are airway inflammation, recurrent bronchospasms, airway hyperresponsiveness (AHR) and mucus hypersecretion. It is known that sphingolipids play a crucial role in pathogenesis of bronchial asthma. In previous studies we showed that the acid sphingomyelinase (ASM), an enzyme, which catalyzes the hydrolysis of sphingomyelin to ceramide, influences the severity of bronchial asthma. ASM influences the adaptive immune system and ASM-deficient TH2-cells show low levels of IL-4-production and IL-4-secretion. This phenotype can be mirrored with functional ASM inhibition via amitriptyline. Additionally, ASM-deficiency in mice results in a protection in an experimental asthma model. Up to now, the underlying mechanisms of decreased IL-4-production are unknown. Therefore, we defined three major aims for this project: 1. How does the acid sphingomyelinase influence T cell activation and IL-4-protein synthesis? We demonstrated that ASM-deficiency causes a significant reduction of IL-4-gene expression and consecutive IL-4-secretion. Therefore, we want to investigate the influence of ASM on classical Th2 pathways, including the role of ASM and receptor activation in lipid rafts. Using next generation sequencing and phosphoproteomics, we will identify alternative ASM regulated Th2 pathways. 2. Can functional ASM inhibitors mimic the effect of genetic ASM deficiency? In analogy to aim 1, we will investigate if ASM inhibition via functional ASM inhibitors has similar effects like a genetic ASM-deficiency in T cells or even additional impacts on TH2-directed pathways. Therefore, ASM inhibitors could serve as novel therapeutical strategies in bronchial asthma. Moreover, we will define whether the findings of the murine system can be translated into human T cells by using stimulated cells of healthy controls and asthmatic patients. 3. How does T-cell specific ASM deficiency/inhibition influence disease activity in bronchial asthma? As proof of principle experiments, we would like to perform ovalbumin/house dust mite-induced experimental asthma models in mice with a T cell specific deletion of ASM as well as in wildtype mice with functional ASM inhibition via inhaled amitriptyline. Thus, the 3rd aim will define the clinical relevance of inhalative ASM inhibition in experimental asthma. Taken together, our project will identify the molecular role of acid sphingomyelinase in TH2-directed asthma and thereby establish functional ASM inhibition as a new therapeutical strategy in bronchial asthma.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Eva Verjans, until 3/2024