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Advances in Sphingolipid Biology: Implications for Cellular Signaling and Immune Response

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Dr. Avota Elita

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Institute for Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany
Interests: T cell sphingolipid metabolism

Special Issue Information

Dear Colleagues,

Sphingolipids are key membrane components and therefore crucial in defining the biophysical properties of cellular membranes. Beyond the crucial role of sphingolipids as important structural lipids, they also exhibit signaling capacity. Most notably, bioactive sphingolipid metabolites, such as ceramides, sphingosine, and sphingosine-1-phosphate (S1P), can act as signaling entities themselves or execute signaling by regulating cellular protein compartmentalization and thereby activity. Very complex networks of sphingolipid-synthesizing and -metabolizing enzymes are involved in the homeostatic control of sphingolipid levels. Defects in sphingolipid homeostasis have been associated with several human diseases due to neurological and immune pathophysiology, as well as cancer and infection diseases, thus underlining the importance of sphingolipid research. Structural diversity, subcellular distribution complexity, and the highly dynamic metabolism of sphingolipids are only a few of the challenges that ought to be met in studies on the biological functions of sphingolipids. An even more complex picture involves evolving the study of sphingolipids on an organismic level. Their highly specific pattern of sphingolipid content controls cellular heterogenicity and differentiation fate, the processes of which are not fully understood. Studies on a multidisciplinary approach of sphingolipids require biochemical, biophysical, and “omics” approaches applied in biological systems.

This Special Issue invites manuscripts that focus on the sphingolipid role in cellular signaling and immune responses in a cell-specific manner. The profiles of sphingolipid-interacting proteins and other lipids in cellular membranes of different types of immune cells are poorly characterized. Therefore, manuscripts that derive from multidisciplinary efforts to reveal the molecular mechanisms of the sphingolipid role in pathophysiological conditions or in cellular defense against invading pathogens are especially welcome.

Dr. Avota Elita
Guest Editor

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Keywords

sphingolipids
ceramides
sphingomyelinases
ceramidases
sphingomyelin
lipid homeostasis
signaling
immune response

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29 pages, 7644 KiB

Open AccessArticle

The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells

by Rebekka Schempp, Janna Eilts, Marie Schöl, Maria Fernanda Grijalva Yépez, Agnes Fekete, Dominik Wigger, Fabian Schumacher, Burkhard Kleuser, Marco van Ham, Lothar Jänsch, Markus Sauer and Elita Avota

Int. J. Mol. Sci. 2024, 25(6), 3247; https://doi.org/10.3390/ijms25063247 - 13 Mar 2024

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Abstract

The accumulation of lipid droplets (LDs) and ceramides (Cer) is linked to non-alcoholic fatty liver disease (NAFLD), regularly co-existing with type 2 diabetes and decreased immune function. Chronic inflammation and increased disease severity in viral infections are the hallmarks of the obesity-related immunopathology. The upregulation of neutral sphingomyelinase-2 (NSM2) has shown to be associated with the pathology of obesity in tissues. Nevertheless, the role of sphingolipids and specifically of NSM2 in the regulation of immune cell response to a fatty acid (FA) rich environment is poorly studied. Here, we identified the presence of the LD marker protein perilipin 3 (PLIN3) in the intracellular nano-environment of NSM2 using the ascorbate peroxidase APEX2-catalyzed proximity-dependent biotin labeling method. In line with this, super-resolution structured illumination microscopy (SIM) shows NSM2 and PLIN3 co-localization in LD organelles in the presence of increased extracellular concentrations of oleic acid (OA). Furthermore, the association of enzymatically active NSM2 with isolated LDs correlates with increased Cer levels in these lipid storage organelles. NSM2 enzymatic activity is not required for NSM2 association with LDs, but negatively affects the LD numbers and cellular accumulation of long-chain unsaturated triacylglycerol (TAG) species. Concurrently, NSM2 expression promotes mitochondrial respiration and fatty acid oxidation (FAO) in response to increased OA levels, thereby shifting cells to a high energetic state. Importantly, endogenous NSM2 activity is crucial for primary human CD4⁺ T cell survival and proliferation in a FA rich environment. To conclude, our study shows a novel NSM2 intracellular localization to LDs and the role of enzymatically active NSM2 in metabolic response to enhanced FA concentrations in T cells. Full article

(This article belongs to the Special Issue Advances in Sphingolipid Biology: Implications for Cellular Signaling and Immune Response)

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13 pages, 2363 KiB

Open AccessArticle

Sphingosine Prevents Rhinoviral Infections

by Judith Lang, Matthias Soddemann, Michael J. Edwards, Gregory C. Wilson, Karl S. Lang and Erich Gulbins

Int. J. Mol. Sci. 2024, 25(5), 2486; https://doi.org/10.3390/ijms25052486 - 20 Feb 2024

Viewed by 530

Abstract

Rhinoviral infections cause approximately 50% of upper respiratory tract infections and novel treatment options are urgently required. We tested the effects of 10 μM to 20 μM sphingosine on the infection of cultured and freshly isolated human cells with minor and major group rhinovirus in vitro. We also performed in vivo studies on mice that were treated with an intranasal application of 10 μL of either a 10 μM or a 100 μM sphingosine prior and after infection with rhinovirus strains 1 and 2 and determined the infection of nasal epithelial cells in the presence or absence of sphingosine. Finally, we determined and characterized a direct binding of sphingosine to rhinovirus. Our data show that treating freshly isolated human nasal epithelial cells with sphingosine prevents infections with rhinovirus strains 2 (minor group) and 14 (major group). Nasal infection of mice with rhinovirus 1b and 2 is prevented by the intranasal application of sphingosine before or as long as 8 h after infection with rhinovirus. Nasal application of the same doses of sphingosine exerts no adverse effects on epithelial cells as determined by hemalaun and TUNEL stainings. The solvent, octylglucopyranoside, was without any effect in vitro and in vivo. Mechanistically, we demonstrate that the positively charged lipid sphingosine binds to negatively charged molecules in the virus, which seems to prevent the infection of epithelial cells. These findings indicate that exogenous sphingosine prevents infections with rhinoviruses, a finding that could be therapeutically exploited. In addition, we demonstrated that sphingosine has no obvious adverse effects on the nasal mucosa. Sphingosine prevents rhinoviral infections by a biophysical mode of action, suggesting that sphingosine could serve to prevent many viral infections of airways and epithelial cells in general. Future studies need to determine the molecular mechanisms of how sphingosine prevents rhinoviral infections and whether sphingosine also prevents infections with other viruses inducing respiratory tract infections. Furthermore, our studies do not provide detailed pharmacokinetics that are definitely required before the further development of sphingosine. Full article

(This article belongs to the Special Issue Advances in Sphingolipid Biology: Implications for Cellular Signaling and Immune Response)

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Advances in Sphingolipid Biology: Implications for Cellular Signaling and Immune Response

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