Inhibition of acid sphingomyelinase increases regulatory T cells in humans

Wiese, Teresa; Dennstädt, Fabio; Hollmann, Claudia; Stonawski, Saskia; Wurst, Catherina; Fink, J. Stephen; Gorte, E.; Mandasari, Putri; Domschke, Katharina; Hommers, Leif; Vanhove, Bernard; Schumacher, Fabian; Kleuser, Burkhard; Seibel, Jürgen; Rohr, Jan; Buttmann, Mathias; Menke, Andreas; Schneider‐Schaulies, Jürgen; Beyersdorf, Niklas

doi:10.1093/braincomms/fcab020

Cited by 13 publications

(14 citation statements)

References 50 publications

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“…Concomitantly, decreased frequencies of Tregs in the spleen were observed in mice with T-cell-specific ASM overexpression [74]. Regarding this, there is already a study performed in humans that supports these findings [79]. In this study the pharmacological inhibition of ASM increased the frequency of Tregs among human CD4 + T cells [79].…”

Section: Cd4 + T Cellssupporting

confidence: 66%

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Acid Sphingomyelinase Deficiency: A Clinical and Immunological Perspective

Pinto

Sousa

Ghilas

et al. 2021

IJMS

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Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of acid sphingomyelinase (ASM) enzyme, leading to the accumulation of varying degrees of sphingomyelin. Lipid storage leads to foam cell infiltration in tissues, and clinical features including hepatosplenomegaly, pulmonary insufficiency and in some cases central nervous system involvement. ASM enzyme replacement therapy is currently in clinical trial being the first treatment addressing the underlying pathology of the disease. Therefore, presently, it is critical to better comprehend ASMD to improve its diagnose and monitoring. Lung disease, including recurrent pulmonary infections, are common in ASMD patients. Along with lung disease, several immune system alterations have been described both in patients and in ASMD animal models, thus highlighting the role of ASM enzyme in the immune system. In this review, we summarized the pivotal roles of ASM in several immune system cells namely on macrophages, Natural Killer (NK) cells, NKT cells, B cells and T cells. In addition, an overview of diagnose, monitoring and treatment of ASMD is provided highlighting the new enzyme replacement therapy available.

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Section: Cd4 + T Cellssupporting

confidence: 66%

“…Regarding this, there is already a study performed in humans that supports these findings [ 79 ]. In this study the pharmacological inhibition of ASM increased the frequency of Tregs among human CD4 + T cells [ 79 ].…”

Section: Acid Sphingomyelinase Role In the Immune Systemsupporting

confidence: 64%

Acid Sphingomyelinase Deficiency: A Clinical and Immunological Perspective

Pinto

Sousa

Ghilas

et al. 2021

IJMS

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“…Specifically, the pharmacological and genetic inhibition of acid sphingomyelinase correlated with an increase in Foxp3 + regulatory T cells, possibly involving CD28 co-stimulation. These observations point to a negative role of acid sphingomyelinase on Foxp3 + regulatory T cells [178][179][180].…”

Section: Lymphocytes: T-cells B-cells Natural Killer Cellsmentioning

confidence: 87%

“…Additionally, changes in acid sphingomyelinase levels have been reported to alter the number of regulatory T cells in vitro and in vivo [178][179][180]. Specifically, the pharmacological and genetic inhibition of acid sphingomyelinase correlated with an increase in Foxp3 + regulatory T cells, possibly involving CD28 co-stimulation.…”

Section: Lymphocytes: T-cells B-cells Natural Killer Cellsmentioning

confidence: 99%

Sphingolipids in Hematopoiesis: Exploring Their Role in Lineage Commitment

Raza

Salman

Luberto

2021

Cells

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Sphingolipids, associated enzymes, and the sphingolipid pathway are implicated in complex, multifaceted roles impacting several cell functions, such as cellular homeostasis, apoptosis, cell differentiation, and more through intrinsic and autocrine/paracrine mechanisms. Given this broad range of functions, it comes as no surprise that a large body of evidence points to important functions of sphingolipids in hematopoiesis. As the understanding of the processes that regulate hematopoiesis and of the specific characteristics that define each type of hematopoietic cells is being continuously refined, the understanding of the roles of sphingolipid metabolism in hematopoietic lineage commitment is also evolving. Recent findings indicate that sphingolipid alterations can modulate lineage commitment from stem cells all the way to megakaryocytic, erythroid, myeloid, and lymphoid cells. For instance, recent evidence points to the ability of de novo sphingolipids to regulate the stemness of hematopoietic stem cells while a substantial body of literature implicates various sphingolipids in specialized terminal differentiation, such as thrombopoiesis. This review provides a comprehensive discussion focused on the mechanisms that link sphingolipids to the commitment of hematopoietic cells to the different lineages, also highlighting yet to be resolved questions.

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“…For instance, CD4 + Foxp3 + regulatory T cells (T reg ) protecting the body from autoimmunity and immunopathology have been shown to have a much higher ceramide content than CD4 + Foxp3 − conventional (T conv ) T helper cells [ 5 , 6 ]. In humans, the incorporation of clickable ceramide is positively correlated with effector/memory differentiation of both T reg and T conv [ 7 ]. While the determination of cellular ceramide content using mass spectrometry reflects ceramide content at the population level, minimally modified ceramides suitable for click chemistry allow the ceramide content to be determined at the single-cell level using flow cytometry, fluorescence, or confocal microscopy [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Ceramide-Containing Liposomes as Membrane Models for Different T Cell Subpopulations

Eder

Hollmann

Mandasari

et al. 2022

JFB

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A fine balance of regulatory (Treg) and conventional CD4+ T cells (Tconv) is required to prevent harmful immune responses, while at the same time ensuring the development of protective immunity against pathogens. As for many cellular processes, sphingolipid metabolism also crucially modulates the Treg/Tconv balance. However, our understanding of how sphingolipid metabolism is involved in T cell biology is still evolving and a better characterization of the tools at hand is required to advance the field. Therefore, we established a reductionist liposomal membrane model system to imitate the plasma membrane of mouse Treg and Tconv with regards to their ceramide content. We found that the capacity of membranes to incorporate externally added azide-functionalized ceramide positively correlated with the ceramide content of the liposomes. Moreover, we studied the impact of the different liposomal preparations on primary mouse splenocytes in vitro. The addition of liposomes to resting, but not activated, splenocytes maintained viability with liposomes containing high amounts of C16-ceramide being most efficient. Our data thus suggest that differences in ceramide post-incorporation into Treg and Tconv reflect differences in the ceramide content of cellular membranes.

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Inhibition of acid sphingomyelinase increases regulatory T cells in humans

Cited by 13 publications

References 50 publications

Acid Sphingomyelinase Deficiency: A Clinical and Immunological Perspective

Acid Sphingomyelinase Deficiency: A Clinical and Immunological Perspective

Sphingolipids in Hematopoiesis: Exploring Their Role in Lineage Commitment

Synthesis and Characterization of Ceramide-Containing Liposomes as Membrane Models for Different T Cell Subpopulations

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