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Article

Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via Inhibition of Toll-Like Receptor (TLR) 4 and TLR2 Signaling and Modulation of Macrophage Polarization

1
MAX BioPharma Inc., Santa Monica, CA 90404, USA
2
Laboratory of Cellular & Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
3
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Yu-Hsiang Kuan, Chunjung Chen, Se-Kwon Kim and Andreas Weigert
Int. J. Mol. Sci. 2022, 23(10), 5478; https://doi.org/10.3390/ijms23105478
Received: 8 April 2022 / Revised: 4 May 2022 / Accepted: 11 May 2022 / Published: 13 May 2022
(This article belongs to the Special Issue Bioactive Compounds: Potential New Anti-inflammatory Drugs)
Inflammatory responses by the innate and adaptive immune systems protect against infections and are essential to health and survival. Many diseases including atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and obesity involve persistent chronic inflammation. Currently available anti-inflammatory agents, including non-steroidal anti-inflammatory drugs, steroids, and biologics, are often unsafe for chronic use due to adverse effects. The development of effective non-toxic anti-inflammatory agents for chronic use remains an important research arena. We previously reported that oral administration of Oxy210, a semi-synthetic oxysterol, ameliorates non-alcoholic steatohepatitis (NASH) induced by a high-fat diet in APOE*3-Leiden.CETP humanized mouse model of NASH and inhibits expression of hepatic and circulating levels of inflammatory cytokines. Here, we show that Oxy210 also inhibits diet-induced white adipose tissue inflammation in APOE*3-Leiden.CETP mice, evidenced by the inhibition of adipose tissue expression of IL-6, MCP-1, and CD68 macrophage marker. Oxy210 and related analogs exhibit anti-inflammatory effects in macrophages treated with lipopolysaccharide in vitro, mediated through inhibition of toll-like receptor 4 (TLR4), TLR2, and AP-1 signaling, independent of cyclooxygenase enzymes or steroid receptors. The anti-inflammatory effects of Oxy210 are correlated with the inhibition of macrophage polarization. We propose that Oxy210 and its structural analogs may be attractive candidates for future therapeutic development for targeting inflammatory diseases. View Full-Text
Keywords: Oxy210; oxysterols; inflammation; toll-like receptors (TLRs); anti-inflammatory agents; macrophage polarization; oxysterol therapeutics; white adipose tissue Oxy210; oxysterols; inflammation; toll-like receptors (TLRs); anti-inflammatory agents; macrophage polarization; oxysterol therapeutics; white adipose tissue
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MDPI and ACS Style

Wang, F.; Stappenbeck, F.; Tang, L.-Y.; Zhang, Y.E.; Hui, S.T.; Lusis, A.J.; Parhami, F. Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via Inhibition of Toll-Like Receptor (TLR) 4 and TLR2 Signaling and Modulation of Macrophage Polarization. Int. J. Mol. Sci. 2022, 23, 5478. https://doi.org/10.3390/ijms23105478

AMA Style

Wang F, Stappenbeck F, Tang L-Y, Zhang YE, Hui ST, Lusis AJ, Parhami F. Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via Inhibition of Toll-Like Receptor (TLR) 4 and TLR2 Signaling and Modulation of Macrophage Polarization. International Journal of Molecular Sciences. 2022; 23(10):5478. https://doi.org/10.3390/ijms23105478

Chicago/Turabian Style

Wang, Feng, Frank Stappenbeck, Liu-Ya Tang, Ying E. Zhang, Simon T. Hui, Aldons J. Lusis, and Farhad Parhami. 2022. "Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via Inhibition of Toll-Like Receptor (TLR) 4 and TLR2 Signaling and Modulation of Macrophage Polarization" International Journal of Molecular Sciences 23, no. 10: 5478. https://doi.org/10.3390/ijms23105478

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