Modulation of Inflammation-Related Lipid Mediator Pathways by Celastrol During Human Macrophage Polarization

Kehong Zhang; Paul Mike Jordan; Simona Pace; Robert K Hofstetter; Markus Werner; Xinchun Chen; Oliver Werz

doi:10.2147/JIR.S356964

Modulation of Inflammation-Related Lipid Mediator Pathways by Celastrol During Human Macrophage Polarization

J Inflamm Res. 2022 Jun 2:15:3285-3304. doi: 10.2147/JIR.S356964. eCollection 2022.

Authors

Kehong Zhang^{1

2}, Paul Mike Jordan¹, Simona Pace¹, Robert K Hofstetter¹, Markus Werner¹, Xinchun Chen², Oliver Werz¹

Affiliations

¹ Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, D-07743, Germany.
² Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, 518000, People's Republic of China.

Abstract

Background and purpose: Celastrol (CS) is a major active ingredient of the Chinese/Asian herb Tripterygium wilfordii that is frequently used as phytomedicine to treat inflammation and autoimmune diseases. We showed before that short-term exposure to CS (1 µM) favorably impacts the biosynthesis of inflammation-related lipid mediators (LM) in human polarized macrophages by modulating the activities of different lipoxygenases (LOXs). However, whether CS regulates the expression of LOXs and other related LM-biosynthetic enzymes during macrophage polarization is unknown. Here, we investigated how CS affects LM-biosynthetic enzyme expression on the protein level and studied concomitant LM signature profiles during polarization of human monocyte-derived macrophages (MDM) towards M1- and M2-like phenotypes.

Methods and results: We used LM metabololipidomics to study the long-term effects of CS on LM profile signatures after manipulation of human monocyte-derived macrophages (MDM) during polarization. Exposure of MDM to low concentrations of CS (ie, 0.2 µM) during polarization to an inflammatory M1 phenotype potently suppressed the formation of pro-inflammatory cyclooxygenase (COX)- and 5-LOX-derived LM, especially prostaglandin (PG)E₂. Notably, gene and enzyme expression of COX-2 and microsomal PGE₂ synthase (mPGES)-1 as well as M1 markers were strongly decreased by CS during M1-MDM polarization, along with impaired activation of nuclear factor-κB and p38 mitogen-activated protein kinase. During IL-4-induced M2 polarization, CS decreased the capacity of the resulting M2-MDM to generate pro-inflammatory COX and 5-LOX products as well but it also reduced the formation of 12/15-LOX products and specialized pro-resolving mediators, without affecting the levels of liberated fatty acid substrates.

Conclusion: Depending on the timing and concentration, CS not only favorably affects LOX activities in macrophages but also the expression of LM-biosynthetic enzymes during macrophage polarization connected to changes of inflammation-related LM which might be of relevance for potential application of CS to treat inflammatory disorders.

Keywords: celastrol; cyclooxygenase; inflammation; lipid mediators; lipoxygenase; macrophages; specialized pro-resolving mediators.

Grants and funding

This work was supported by the Free State of Thuringia and the European Social Fund (2019 FGR 0095) and by the Deutsche Forschungsgemeinschaft (DFG), Collaborative Research Center SFB 1278 “PolyTarget” (project number 316213987, project A04) and - SFB 1127 “ChemBioSys” (project number 239748522, project A04).