Trans -10-hydroxy-2-decenoic acid protects against LPS-induced neuroinflammation through FOXO1-mediated activation of au
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ORIGINAL CONTRIBUTION
Trans‑10‑hydroxy‑2‑decenoic acid protects against LPS‑induced neuroinflammation through FOXO1‑mediated activation of autophagy Mengmeng You1 · Zhuoning Miao1 · Jing Tian1 · Fuliang Hu1 Received: 1 May 2019 / Accepted: 22 October 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract Purpose Neuroinflammation is thought to be associated with the pathogenesis of a series of neurodegenerative diseases. We have previously reported that royal jelly (RJ) has an anti-inflammatory effect on microglial BV-2 cells. However, components contributing to the effect of RJ were largely unexplored. The aim of this study was to assess whether trans-10-hydroxy2-decenoic acid (10-HDA), the exclusive fatty acid in RJ, can alleviate neuroinflammation and to further explore the underlying mechanisms. Methods Immunohistochemistry staining, ELISA, qRT-PCR and Western blot were used to assess the effect of 10-HDA on LPS-induced neuroinflammation both in vivo and in vitro. To determine the extent of inflammatory changes after 10-HDA treatment, RNAseq transcriptomic analysis was conducted. Results 10-HDA pretreatment significantly reduced the production of pro-inflammatory mediators in LPS-treated C57BL/6J mice and microglial BV-2 cells. 10-HDA inhibited the activation of the TNF-α/NF-κB axis and NLRP3 inflammasome-IL-1β pathway, which may be the anti-neuroinflammatory mechanism of 10-HDA. We also demonstrated that 10-HDA triggered cell autophagy, as evidenced by elevated levels of microtubule-associated protein 1 light chain 3-II (LC3-II) and decreased expression of SQSTM1. More importantly, 10-HDA increased the transcriptional activity of FOXO1 by increasing FOXO1 nuclear localization. Inhibition of FOXO1 and autophagy using chemical inhibitors markedly blunted the effect of 10-HDA on the TNF-α pathway and NLRP3 inflammasome-IL-1β pathway, indicating that 10-HDA alleviates neuroinflammation in BV-2 cells by modulating FOXO1-mediated autophagy. Conclusions 10-HDA may be a promising agent for various neuroinflammation-associated diseases. Keywords Trans-10-hydroxy-2-decenoic acid · Neuroinflammation · TNF-α/NF-κB axis · NLRP3 inflammasome · Autophagy · FOXO1 Abbreviations AD Alzheimer’s disease PD Parkinson’s disease CNS Central nervous system ROS Reactive oxygen species NO Nitric oxide NLRP3 Nod-like receptor protein 3 IL-1β Interleukin-1β Atgs Autophagy-related genes Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00394-019-02128-9) contains supplementary material, which is available to authorized users.
NSAIDs Nonsteroidal anti-inflammatory drugs RJ Royal jelly 10-HDA Trans-10-hydroxy-2-decenoic acid LPS Lipopolysaccharide CM Conditioned medium NF-κB Nuclear factor-κB TNF-α Tumour necrosis factor-α Baf A1 Bafilomycin A1 GFAP Glial fibrillary acidic protein Iba1 Ionized calcium-binding adaptor molecule 1 ULK Unc-51-like autophagy-activating kinase FOXO1 Forkhead box protein 1
* Fuliang Hu [email protected] 1
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