Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T‐cell migration into tumors

Akéus, Paulina; Szeponik, Louis; Langenes, Veronica; Karlsson, Viktoria; Sundström, Patrik; Lindskog, Elinor Bexe; Tallon, Carolyn; Slusher, Barbara S.; Quiding‐Järbrink, Marianne

doi:10.1002/eji.202149208

Cited by 4 publications

(1 citation statement)

References 52 publications

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“…Likewise, downregulation of CerS promotes the development of tumors with prolonged inflammation and dysregulated ER stress 157 , 158 , and the acidic tumor microenvironment can activate aSMase and induce metalloproteinase-9, which promotes metastasis and immune evasion of tumors 159 , 160 . Modulation of nSMase2 can enhance the antitumor response to anti-PD-1 therapy 161 , but tumor-infiltrating T regs can reduce the expression of endothelial nSMase2, preventing lymphocyte migration; 162 moreover, enriched S1P and LPA in the tumor microenvironment can reprogram the antitumor activity of infiltrated lymphocytes 29 , 163 . The results suggest that targeted sphingolipid modulation in tumor patients can provide a strategy for cancer therapy and can promote the survival of tumor patients 151 .…”

Section: Disrupted Homeostasis Of Sphingolipids In Diseasementioning

confidence: 99%

Functional roles of sphingolipids in immunity and their implication in disease

Lee

Bae

2023

Exp Mol Med

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Sphingolipids, which are components of cellular membranes and organ tissues, can be synthesized or degraded to modulate cellular responses according to environmental cues, and the balance among the different sphingolipids is important for directing immune responses, regardless of whether they originate, as intra- or extracellular immune events. Recent progress in multiomics-based analyses and methodological approaches has revealed that human health and diseases are closely related to the homeostasis of sphingolipid metabolism, and disease-specific alterations in sphingolipids and related enzymes can be prognostic markers of human disease progression. Accumulating human clinical data from genome-wide association studies and preclinical data from disease models provide support for the notion that sphingolipids are the missing pieces that supplement our understanding of immune responses and diseases in which the functions of the involved proteins and nucleotides have been established. In this review, we analyze sphingolipid-related enzymes and reported human diseases to understand the important roles of sphingolipid metabolism. We discuss the defects and alterations in sphingolipid metabolism in human disease, along with functional roles in immune cells. We also introduce several methodological approaches and provide summaries of research on sphingolipid modulators in this review that should be helpful in studying the roles of sphingolipids in preclinical studies for the investigation of experimental and molecular medicines.

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Section: Disrupted Homeostasis Of Sphingolipids In Diseasementioning

confidence: 99%

Functional roles of sphingolipids in immunity and their implication in disease

Lee

Bae

2023

Exp Mol Med

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Lack of cellular prion protein causes Amyloid β accumulation, increased extracellular vesicle abundance, and changes to exosome biogenesis proteins

Johansson,

Reyes,

Ali

et al. 2024

Mol Cell Biochem

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Alzheimer's disease (AD) progression is closely linked to the propagation of pathological Amyloid β (Aβ), a process increasingly understood to involve extracellular vesicles (EVs), namely exosomes. The specifics of Aβ packaging into exosomes remain elusive, although evidence suggests an ESCRT (Endosomal Sorting Complex Required for Transport)-independent origin to be responsible in spreading of AD pathogenesis. Intriguingly, PrPC, known to influence exosome abundance and bind oligomeric Aβ (oAβ), can be released in exosomes via both ESCRT-dependent and ESCRT-independent pathways, raising questions about its role in oAβ trafficking. Thus, we quantified Aβ levels within EVs, cell medium, and intracellularly, alongside exosome biogenesis-related proteins, following deletion or overexpression of PrPC. The same parameters were also evaluated in the presence of specific exosome inhibitors, namely Manumycin A and GW4869. Our results revealed that deletion of PrPC increases intracellular Aβ accumulation and amplifies EV abundance, alongside significant changes in cellular levels of exosome biogenesis-related proteins Vps25, Chmp2a, and Rab31. In contrast, cellular expression of PrPC did not alter exosomal Aβ levels. This highlights PrPC’s influence on exosome biogenesis, albeit not in direct Aβ packaging. Additionally, our data confirm the ESCRT-independent exosome release of Aβ and we show a direct reduction in Chmp2a levels upon oAβ challenge. Furthermore, inhibition of opposite exosome biogenesis pathway resulted in opposite cellular PrPC levels. In conclusion, our findings highlight the intricate relationship between PrPC, exosome biogenesis, and Aβ release. Specifically, they underscore PrPC’s critical role in modulating exosome-associated proteins, EV abundance, and cellular Aβ levels, thereby reinforcing its involvement in AD pathogenesis. Graphical abstract There are two main exosome biogenesis pathways: ESCRT dependent and ESCRT independent. In this study, we explored the effect of the cellular prion protein (PrPC) on the release of Amyloid β via exosomes. Our findings demonstrate that Amyloid β mainly is released via an ESCRT-independent pathway, independent of PrPC. However, lack of PrPC resulted in upregulation of the ESCRT-dependent proteins Tsg101 and VPS25, a decrease in Chmp2a, and an overall increase in extracellular vesicles. Lack of PrPC also caused an accumulation of cellular, but not exosomal, Amyloid β.

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