Platelet-Activating Factor Deteriorates Lysophosphatidylcholine-Induced Demyelination Via Its Receptor-Dependent and -In
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ORIGINAL ARTICLE
Platelet-Activating Factor Deteriorates Lysophosphatidylcholine-Induced Demyelination Via Its Receptor-Dependent and -Independent Effects Zhisen Tian 1,2 & Tianci Chu 2 & Lisa B. E. Shields 3 & Qingsan Zhu 1 & Yi Ping Zhang 3 & Maiying Kong 4 & Gregory N. Barnes 2,5,6 & Yuanyi Wang 7 & Christopher B. Shields 3,8 & Jun Cai 2,6 Received: 24 October 2019 / Accepted: 26 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Accumulating evidence suggests that platelet-activating factor (PAF) increases the inflammatory response in demyelinating diseases such as multiple sclerosis. However, PAF receptor (PAFR) antagonists do not show therapeutic efficacy for MS, and its underlying mechanisms remain poorly understood. In the present study, we investigated the effects of PAF on an ex vivo demyelination cerebellar model following lysophosphatidylcholine (LPC, 0.5 mg/mL) application using wild-type and PAFR conventional knockout (PAFR-KO) mice. Demyelination was induced in cerebellar slices that were cultured with LPC for 18 h. Exogenous PAF (1 μM) acting on cerebellar slices alone did not cause demyelination but increased the severity of LPC-induced demyelination in both wild-type and PAFR-KO mice. LPC inhibited the expression of PAF-AH, MBP, TNF-α, and TGF-β1 but facilitated the expression of IL-1β and IL-6 in wild-type preparations. Of note, exogenous PAF stimulated microglial activation in both wild-type and PAFR-KO mice. The subsequent inflammatory cytokines TNFα, IL-1β, and IL-6 as well as the antiinflammatory cytokine TGF-β1 demonstrated a diverse transcriptional profile with or without LPC treatment. PAF promoted TNF-α expression and suppressed TGF-β1 expression indiscriminately in wild-type and knockout slices; however, transcription of IL-1β and IL-6 was not significantly affected in both slices. The syntheses of IL-1β and IL-6 were significantly increased in LPC-induced demyelination preparations without PAF but showed a redundancy in PAF-treated wild-type and knockout slices. These data suggest that PAF can play a detrimental role in LPC-induced demyelination probably due to a redundant response of PAFR-dependent and PAFR-independent effects on inflammatory cytokines. Keywords Demyelination . Lysophosphatidylcholine . Platelet-activating factor . Platelet-activating factor receptor . Cytokine . Ex vivo Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02003-3) contains supplementary material, which is available to authorized users. * Qingsan Zhu [email protected] * Yuanyi Wang [email protected]
4
Department of Bioinformatics and Biostatistics, University of Louisville School of Public Health & Information Sciences, Louisville, KY 40202, USA
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Department of Neurology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Department of Spine Surgery, The First Hospit
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