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Article

S1P Lyase Deficiency in the Brain Promotes Astrogliosis and NLRP3 Inflammasome Activation via Purinergic Signaling

by
Shah Alam
1,
Sumaiya Yasmeen Afsar
1,
Maya Anik Wolter
1,
Luisa Michelle Volk
2,
Daniel Nicolae Mitroi
1,†,
Dagmar Meyer zu Heringdorf
2 and
Gerhild van Echten-Deckert
1,*
1
LIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53115 Bonn, Germany
2
Institute for General Pharmacology and Toxicology, University Hospital, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
†
Current address: AbbVie, Newport Beach, CA 92612, USA.
Cells 2023, 12(14), 1844; https://doi.org/10.3390/cells12141844
Submission received: 2 May 2023 / Revised: 19 June 2023 / Accepted: 6 July 2023 / Published: 13 July 2023
(This article belongs to the Special Issue Astroglial (Patho)Physiology)
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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.
Keywords: sphingosine 1-phosphate (S1P); S1P-lyase (SGPL1); astrogliosis; P2Y1 receptor (P2Y1R); neuroinflammation; NLRP3 inflammasome; DDX3X; calcium; calbindin sphingosine 1-phosphate (S1P); S1P-lyase (SGPL1); astrogliosis; P2Y1 receptor (P2Y1R); neuroinflammation; NLRP3 inflammasome; DDX3X; calcium; calbindin

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MDPI and ACS Style

Alam, S.; Afsar, S.Y.; Wolter, M.A.; Volk, L.M.; Mitroi, D.N.; Meyer zu Heringdorf, D.; van Echten-Deckert, G. S1P Lyase Deficiency in the Brain Promotes Astrogliosis and NLRP3 Inflammasome Activation via Purinergic Signaling. Cells 2023, 12, 1844. https://doi.org/10.3390/cells12141844

AMA Style

Alam S, Afsar SY, Wolter MA, Volk LM, Mitroi DN, Meyer zu Heringdorf D, van Echten-Deckert G. S1P Lyase Deficiency in the Brain Promotes Astrogliosis and NLRP3 Inflammasome Activation via Purinergic Signaling. Cells. 2023; 12(14):1844. https://doi.org/10.3390/cells12141844

Chicago/Turabian Style

Alam, Shah, Sumaiya Yasmeen Afsar, Maya Anik Wolter, Luisa Michelle Volk, Daniel Nicolae Mitroi, Dagmar Meyer zu Heringdorf, and Gerhild van Echten-Deckert. 2023. "S1P Lyase Deficiency in the Brain Promotes Astrogliosis and NLRP3 Inflammasome Activation via Purinergic Signaling" Cells 12, no. 14: 1844. https://doi.org/10.3390/cells12141844

APA Style

Alam, S., Afsar, S. Y., Wolter, M. A., Volk, L. M., Mitroi, D. N., Meyer zu Heringdorf, D., & van Echten-Deckert, G. (2023). S1P Lyase Deficiency in the Brain Promotes Astrogliosis and NLRP3 Inflammasome Activation via Purinergic Signaling. Cells, 12(14), 1844. https://doi.org/10.3390/cells12141844

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