Immunoregulatory role of acid sphingomyelinase in allergic asthma

Abstract

Acid sphingomyelinase (ASM) is one of the enzymes that catalyzes the breakdown of sphingomyelin to ceramide and phosphorylcholine. In this study, we aimed at elucidating the role of ASM in allergic asthma. We used an ovalbumin-induced murine model of asthma where we compared wild-type and ASM-deficient mice. In wild-type mice, secretory ASM activity in the bronchoalveolar lavage fluid was increased in the acute ovalbumin model, but not in a tolerogenic model. Furthermore, in the absence of ASM, the serum IgE level was reduced, compared with wildtype mice, while an accumulation of interstitial macrophages and foreign antigen-induced regulatory T cells along with exhausted CD4 + PD1 + T cells was observed in the lungs of ASM À/À mice. In conclusion, in the absence of ASM, we observed an accumulation of immunosuppressive antigen-induced regulatory T cells expressing Foxp3 and CTLA4 in the lung as well as multinucleated interstitial macrophages and exhausted CD4 + PD1 + T cells associated with inhibition of serum IgE in asthma.

Acid sphingomyelinase regulates TH2 cytokine release and bronchial asthma

“…In that study, Asm was not elevated in the control groups with asthma or adenovirus infections . This is in line with our results demonstrating that asthmatic sensitization and provocation itself does not alter Asm activity, but in contrast to the results by Sopel et al Yang et al stimulated bone marrow‐derived mast cells of WT mice in vitro with antigens, which resulted in an activation of Asm, while Asm inhibition via amitriptyline decreased antigen‐induced Ca 2+ influx and Asm activity. After induction of systemic anaphylaxis, disease activity was less pronounced in Asm −/− animals compared with WT littermates .…”

“…In that study, Asm was not elevated in the control groups with asthma or adenovirus infections. 11 This is in line with our results demonstrating that asthmatic sensitization and provocation itself does not alter Asm activity, but in contrast to the results by Sopel et al 20 In previous studies it was demonstrated that ASM regulates pathogenic T H 1-and T H 17-differentiation and responses, while it enhances regulatory T cell development and function. 35,36 In line with our data, naïve Asm −/− mice had higher numbers of systemic T reg cells.…”

“…Moreover, increased levels of S1P can be found in bronchoalveolar lavage fluid (BALF) of asthmatic patients after allergen provocation . Recently, in a murine 21‐day ovalbumin‐induced asthma model, Sopel et al observed that Asm deficiency reduced IgE serum levels and that it increased regulatory T cells (T reg ), but they found no effect on physiological lung functions, such as airway hyperresponsiveness (AHR) and they did not study T H 2 cells . However, ASM interacts with the intracellular domains of CD3 and CD28 and mediates intracellular signals that control CD4+ T cell activation by generating ceramide including those that are involved in CD4+ T cell proliferation and activation …”

“…19 Recently, in a murine 21-day ovalbumininduced asthma model, Sopel et al observed that Asm deficiency reduced IgE serum levels and that it increased regulatory T cells (T reg ), but they found no effect on physiological lung functions, such as airway hyperresponsiveness (AHR) and they did not study T H 2 cells. 20 However, ASM interacts with the intracellular domains of CD3 and CD28 and mediates intracellular signals that control CD4+ T cell activation by generating ceramide including those that are involved in CD4+ T cell proliferation and activation. 21 These findings raise the hypothesis that Asm is involved in the regulation of the typical T H 2 phenotype and that this is relevant for allergic lung dysfunctions in a typical 35-day asthma model.…”

Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response

“…It is well documented that sphingolipids play vital roles in the regulation of immune and adaptive cell senescence. For example, most sphingolipids were found to be higher in T cells from A compared to Y mice, and the addition of exogenous C2 and C6 ceramide inhibited T cell proliferation ( Kirk and Miller, 1999 ; Martinova, 1998 ; Sopel et al, 2019 ). These data are consistent with our data presented here, demonstrating that age-related ceramide increases may contribute to the proliferative and functional defects observed in aged T cells through the induction of Drp1-mediated mitochondrial fission and mitophagy.…”