Metabolomics Insights of the Immunomodulatory Activities of Phlorizin and Phloretin on Human THP-1 Macrophages

Dihydrochalcones, phlorizin (PZ) and its aglycone phloretin (PT), have evidenced immunomodulatory effects through several mechanisms. However, the differential metabolic signatures that lead to these properties are largely unknown. Since macrophages play an important role in the immune response, our study aimed to characterise human THP-1 macrophages under PZ and PT exposure. A multiplatform-based untargeted metabolomics approach was used to reveal metabolites associated with the anti-inflammatory mechanisms triggered by the dihydrochalcones in LPS-stimulated macrophages, for the first time. Results showed differential phenotypic response in macrophages for all treatments. Dihydrochalcone treatment in LPS-stimulated macrophages mimics the response under normal conditions, suggesting inhibition of LPS response. Antagonistic effects of dihydrochalcones against LPS was mainly observed in glycerophospholipid and sphingolipid metabolism besides promoting amino acid biosynthesis. Moreover, PT showed greater metabolic activity than PZ. Overall, the findings of this study yielded knowledge about the mechanisms of action PZ and PT at metabolic level in modulating inflammatory response in human cells.
This research was funded by EU FEDER funds, Interreg España-Portugal Programme, under the framework of the Project: ref. 0377_IBERPHENOL_6_E; by Xunta de Galicia funds, Spain (CITACA Strategic Partnership, Reference: ED431E 2018/07) and also supported by UIDB/50006/2020 and PTDC/SAU-NUT/30448/2017 with funding from FCT/MCTES through national funds. I. F. acknowledge her Fundação para a Ciência e Tecnologia (FCT) research contract (SFRH/BPD/86173/2012).