Sphingosine Kinases at the Intersection of Pro-Inflammatory LPS and Anti-Inflammatory Endocannabinoid Signaling in BV2 Mouse Microglia Cells
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Published:2023-05-09
Issue:10
Volume:24
Page:8508
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Standoli Sara1ORCID, Rapino Cinzia2ORCID, Di Meo Camilla1ORCID, Rudowski Agnes3, Kämpfer-Kolb Nicole3, Volk Luisa Michelle3, Thomas Dominique45ORCID, Trautmann Sandra45, Schreiber Yannick5, Meyer zu Heringdorf Dagmar3ORCID, Maccarrone Mauro67ORCID
Affiliation:
1. Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, 64100 Teramo, Italy 2. Department of Veterinary Medicine, University of Teramo, 64100 Teramo, Italy 3. Institute of General Pharmacology and Toxicology, University Hospital Frankfurt, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany 4. Institute of Clinical Pharmacology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany 5. Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), 60596 Frankfurt am Main, Germany 6. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy 7. European Center for Brain Research (CERC), Santa Lucia Foundation, Scientific Institute for Research, Hospitalization and Healthcare, 00143 Rome, Italy
Abstract
Microglia, the resident immune cells of the central nervous system, play important roles in brain homeostasis as well as in neuroinflammation, neurodegeneration, neurovascular diseases, and traumatic brain injury. In this context, components of the endocannabinoid (eCB) system have been shown to shift microglia towards an anti-inflammatory activation state. Instead, much less is known about the functional role of the sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) system in microglia biology. In the present study, we addressed potential crosstalk of the eCB and the S1P systems in BV2 mouse microglia cells challenged with lipopolysaccharide (LPS). We show that URB597, the selective inhibitor of fatty acid amide hydrolase (FAAH)—the main degradative enzyme of the eCB anandamide—prevented LPS-induced production of tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β), and caused the accumulation of anandamide itself and eCB-like molecules such as oleic acid and cis-vaccenic acid ethanolamide, palmitoylethanolamide, and docosahexaenoyl ethanolamide. Furthermore, treatment with JWH133, a selective agonist of the eCB-binding cannabinoid 2 (CB2) receptor, mimicked the anti-inflammatory effects of URB597. Interestingly, LPS induced transcription of both SphK1 and SphK2, and the selective inhibitors of SphK1 (SLP7111228) and SphK2 (SLM6031434) strongly reduced LPS-induced TNFα and IL-1β production. Thus, the two SphKs were pro-inflammatory in BV2 cells in a non-redundant manner. Most importantly, the inhibition of FAAH by URB597, as well as the activation of CB2 by JWH133, prevented LPS-stimulated transcription of SphK1 and SphK2. These results present SphK1 and SphK2 at the intersection of pro-inflammatory LPS and anti-inflammatory eCB signaling, and suggest the further development of inhibitors of FAAH or SphKs for the treatment of neuroinflammatory diseases.
Funder
Italian Ministry of University and Research Fondo Sociale Europeo Deutsche Forschungsgemeinschaft Department of Biotechnological and Applied Clinical Sciences—University of L’Aquila Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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