Acid sphingomyelinase regulates T_H 2 cytokine release and bronchial asthma.

Abstract

Allergic diseases and especially allergic asthma are widespread diseases with high prevalence in childhood, but also in adults. Acid sphingomyelinase (ASM) is a key regulator of the sphingolipid pathway. Previous studies defined the association of ASM with the pathogenesis of T_H 1-directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in T_H 2-regulated allergic bronchial asthma. To determine the role of Asm under baseline conditions, wild-type (WT) and Asm^-/- mice were ventilated with a flexiVent setup and bronchial hyperresponsiveness was determined using acetylcholine. Flow cytometry and cytokine measurements in bronchoalveolar lavage fluid and lung tissue were followed by in vitro T_H 2 differentiations with cells from WT and Asm^-/- mice and blockade of Asm with amitriptyline. As proof of principle, we conducted an ovalbumin-induced model of asthma in WT- and Asm^-/-  mice. At baseline, Asm^-/- mice showed better lung mechanics, but unaltered bronchial hyperresponsiveness. Higher numbers of Asm^-/- T cells in bronchoalveolar lavage fluid released lower levels of IL-4 and IL-5, and these results were paralleled by decreased production of typical T_H 2 cytokines in Asm^-/- T lymphocytes in vitro. This phenotype could be imitated by incubation of T cells with amitriptyline. In the ovalbumin asthma model, Asm^-/- animals were protected from high disease activity and showed better lung functions and lower levels of eosinophils and T_H 2 cytokines. Asm deficiency could induce higher numbers of T_H 2 cells in the lung, but those cells release decreased T_H 2 cytokine levels. Hereby, Asm^-/- animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade.