Asaronic Acid Inhibited Glucose-Triggered M2-Phenotype Shift Through Disrupting the Formation of Coordinated Signaling of IL-4Rα-Tyk2-STAT6 and GLUT1-Akt-mTOR-AMPK

Abstract

<jats:p>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.</jats:p>

Overview of multifunctional Tregs in cardiovascular disease: From insights into cellular functions to clinical implications

“…They secrete anti-inflammatory factors such as IL-10, TGF-β, and vascular endothelial growth factor, which have anti-atherosclerotic effects and stabilize plaques. 64 Tregs facilitate the switching of M1 macrophages to M2 macrophages through the release of…”

“…M2 macrophages undergo polarization in response to the cytokines IL‐4 and IL‐13. They secrete anti‐inflammatory factors such as IL‐10, TGF‐β, and vascular endothelial growth factor, which have anti‐atherosclerotic effects and stabilize plaques 64 . Tregs facilitate the switching of M1 macrophages to M2 macrophages through the release of IL‐10, which has a positive effect on preventing the development of atherosclerosis 39 .…”

Perspectives of herbs and their natural compounds, and herb formulas on treating diverse diseases through regulating complicated JAK/STAT signaling

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Lower expression of Hsa_circRNA_102682 in diabetic hyperhomocysteinemia negatively related to creatinemia is associated with TGF‐β and CTGF

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“… 9 CTGF also has the potential to modulate factors such as vascular endothelial growth factor (VEGF) and bone morphogenic proteins. 10 Renal CTGF may serve as an early marker for progression to dysfunction in DN. 11 , 12 …”