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Cited by 18Sphingolipid Metabolism and SignalingNeuroinflammation and Neurodegeneration MechanismsInflammasome and immune disorders

S1P lyase deficiency in the brain promotes astrogliosis and NLRP3 inflammasome activation via purinergic signaling

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Alam, Shah, Afsar, Sumaiya Yasmeen, Wolter, Maya Anik, Volk, Luisa Michelle, Mitroi, Daniel Nicolae, Meyer zu Heringdorf, Dagmar, van Echten-Deckert, Gerhild·2023·Cells
DOI 10.3390/cells12141844PMC PMC10378183
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Abstract

Astrocytes are critical players in brain health and disease. Brain pathologies and lesions are usually accompanied by astroglial alterations known as reactive astrogliosis. Sphingosine 1-phosphate lyase (SGPL1) catalysis, the final step in sphingolipid catabolism, irreversibly cleaves its substrate sphingosine 1-phosphate (S1P). We have shown that neural ablation of SGPL1 causes accumulation of S1P and hence neuronal damage, cognitive deficits, as well as microglial activation. Moreover, the S1P/S1P-receptor signaling axis enhances ATP production in SGPL1-deficient astrocytes. Using immunohistochemical methods as well as RNA Seq and CUT&Tag we show how S1P signaling causes activation of the astrocytic purinoreceptor P2Y1 (P2Y1R). With specific pharmacological agonists and antagonists, we uncover the P2Y1R as the key player in S1P-induced astrogliosis, and DDX3X mediated the activation of the NLRP3 inflammasome, including caspase-1 and henceforward generation of interleukin-1ß (IL-1ß) and of other proinflammatory cytokines. Our results provide a novel route connecting S1P metabolism and signaling with astrogliosis and the activation of the NLRP3 inflammasome, a central player in neuroinflammation, known to be crucial for the pathogenesis of numerous brain illnesses. Thus, our study opens the door for new therapeutic strategies surrounding S1P metabolism and signaling in the brain.

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Sorted by citations

Authors
Alam, S., Afsar, S. Y., Wolter, M. A., Volk, L. M., Mitroi, D. N., Meyer zu Heringdorf, D., & van Echten-Deckert, G.
Affiliations
  • University of Bonn (DE)
  • Goethe University Frankfurt (DE)
  • Institute for General Pharmacology and Toxicology, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany
  • LIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53115 Bonn, Germany
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2023-07-13
Volume
12
Issue
14
Pages
1844
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells12141844
PMC
PMC10378183
OpenAlex
W4384299935
Cited by
18
References
3
Citations by year
2026: 4 · 2025: 8 · 2024: 5 · 2023: 1
FWCI
1.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Deutsche Forschungsgemeinschaft (EC-118/10-1, SFB 1039, TPB07)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
sphingosine-1-phosphate lyase, SGPL1, reactive astrogliosis, astrocytes, NLRP3 inflammasome, purinergic signaling, P2Y1 receptor, DDX3X, caspase-1, IL-1β, neuroinflammation, sphingosine-1-phosphate, microglial activation, cognitive impairment, ATP production
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Brain, Gliosis, Lyases, Lysophospholipids, Sphingosine, Mice, Inflammasomes

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