Abstract
Procyanidins, a subclass of flavonoids found in commonly consumed foods, possess potential anti-inflammatory activity. Manipulation of M1/M2 macrophage homeostasis is an effective strategy for the treatment of metabolic inflammatory diseases. The objective of this study was to determine the effect of procyanidins on macrophage polarization. Procyanidin B2 (PCB2), the most widely distributed natural procyanidins, enhanced the expressions of M2 macrophage markers (Arg1, Ym1, and Fizz1). PCB2 activated peroxisome proliferator-activated receptor γ (PPARγ) activity and increased the expressions of PPARγ target genes (CD36 and ABCG1) in macrophages. Inhibition of PPARγ using siRNA or antagonist GW9662 attenuated the PCB2-induced expressions of M2 macrophage markers. In addition, we identified cognate PPAR-responsive elements (PPREs) within the 5'-flanking regions of the mouse Arg1, Ym1, and Fizz1 genes. Furthermore, macrophages isolated from db/db diabetic mice showed lower expressions of M2 markers. PCB2 effectively restored the Arg1, Ym1, and Fizz1 expressions in a PPARγ-dependent manner. These findings support the notion that PCB2 regulated macrophage M2 polarization via the activation of PPARγ. Our results provide a new mechanism by which procyanidins exert their beneficial anti-inflammatory effects.
Highlights
Macrophages are key cellular components of innate immunity, acting as a main player in the first-line defense against pathogens and the modulation of immunological homeostasis [1]
We examined whether Procyanidin B2 (PCB2) increased the mRNA expression of M2 macrophage marker genes (Ym1, Arg1, and Fizz1)
We treated RAW264.7 cells with PCB2 before the exposure to LPS and found that PCB2 inhibited LPS-stimulated expression of IL-6 and tumor necrosis factor-α (TNF-α), the M1 marker genes (Figure S2). These results indicated that PCB2 promoted M2 macrophages polarization
Summary
Macrophages are key cellular components of innate immunity, acting as a main player in the first-line defense against pathogens and the modulation of immunological homeostasis [1]. Stimulated by lipopolysaccharides (LPS), interferon-γ or tumor necrosis factor-α (TNF-α), M1 macrophages are characterized by high antigen presentation and expressions of pro-inflammatory cytokines [e.g., interleukin (IL)-1β, IL-6, and the cell membrane molecule CD86], playing an important role in host defense against infection [3]. Nuclear factor-kappa B (NF-κB), signal transducer and activator of transcription 1 (STAT1), CCAAT/enhancer binding proteins α (C/EBP-α), C/EBP-δ, interferon regulatory factor 9 (IRF9), and Krüppel-like factor 6 (KLF6) are important transcription factors involved in M1 polarization [6,7,8,9], whereas STAT3, STAT6, C/EBP-β, IRF4, KLF4, GATA binding protein 3 (GATA3), and peroxisome proliferator-activated receptors (PPARs) are associated with M2 polarization [10,11,12,13,14]. Reshaping macrophage polarization could be a potential strategy against metabolic inflammatory diseases
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