Abstract
Macrophage polarization has been implicated in the pathogenesis of metabolic diseases such as obesity, diabetes, and atherosclerosis. Macrophages responsiveness to polarizing signals can result in their functional phenotype shifts. This study examined whether high glucose induced the functional transition of M2 macrophages, which was inhibited by asaronic acid, one of purple perilla constituents. J774A.1 murine macrophages were incubated with 40 ng/mL interleukin (IL)-4 or exposed to 33 mM glucose in the presence of 1-20 μΜ asaronic acid. In macrophages treated with IL-4 for 48 h, asaronic acid further accelerated cellular induction of the M2 markers of IL-10, arginase-1, CD163, and PPARγ via increased IL-4-IL-4Rα interaction and activated Tyk2-STAT6 pathway. Asaronic acid promoted angiogenic and proliferative capacity of M2-polarized macrophages, through increasing expression of VEGF, PDGF, and TGF-β. In glucose-loaded macrophages, there was cellular induction of IL-4, IL-4 Rα, arginase-1, and CD163, indicating that high glucose skewed naïve macrophages toward M2 phenotypes via an IL-4-IL-4Rα interaction. However, asaronic acid inhibited M2 polarization in diabetic macrophages in parallel with inactivation of Tyk2-STAT6 pathway and blockade of GLUT1-mediated metabolic pathway of Akt-mTOR-AMPKα. Consequently, asaronic acid deterred functional induction of COX-2, CTGF, α-SMA, SR-A, SR-B1, and ABCG1 in diabetic macrophages with M2 phenotype polarity. These results demonstrated that asaronic acid allayed glucose-activated M2-phenotype shift through disrupting coordinated signaling of IL-4Rα-Tyk2-STAT6 in parallel with GLUT1-Akt-mTOR-AMPK pathway. Thus, asaronic acid has therapeutic potential in combating diabetes-associated inflammation, fibrosis, and atherogenesis through inhibiting glucose-evoked M2 polarization.
Highlights
Macrophage polarization and functions are tightly controlled through the activation of various inter-connected pathways in several physiologic and pathologic states [1,2]
1-20 μM asaronic acid dose-dependently curtailed the concurrent increase glucose (Figure 5D). These results showed that asaronic acid deterred glucose-stimulated induction of in the IL-4 receptor Rα (IL-4Rα) induction by glucose (Figure 5D)
(7) Asaronic acid encumbered the activation of tyrosine kinase 2 (Tyk2), STAT6, Akt, mammalian target of rapamycin complex (mTOR), and AMPKα as well as glucose transporter 1 (GLUT1) induction in glucose-loaded macrophages
Summary
Macrophage polarization and functions are tightly controlled through the activation of various inter-connected pathways in several physiologic and pathologic states [1,2]. The STAT3/ STAT6 activation by interleukin (IL)-4, IL-13, and IL-10 induces M2 macrophage polarization, leading to tissue remodeling. Peroxisome proliferator-activated receptor γ (PPARγ) induces human monocytes toward an anti-inflammatory M2 phenotype. The balance between M1 and M2 macrophages is closely regulated in normal tissues and governs the fate of an organ in inflammation or injury [5]. Wound-healing macrophages produce elevated levels of growth factors such as platelet-derived growth factor (PDGF), insulin-like growth factor 1, vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β1 [9,10], which aid in cellular proliferation, granulation, tissue formation, and angiogenesis. The diversity of macrophage phenotypes in vivo remains to be fully characterized
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