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Article

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

Department of Food Science and Nutrition and The Korean Institute of Nutrition, Hallym University, Chuncheon 24252, Korea
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Author to whom correspondence should be addressed.
Nutrients 2020, 12(7), 2006; https://doi.org/10.3390/nu12072006
Received: 2 June 2020 / Revised: 21 June 2020 / Accepted: 3 July 2020 / Published: 6 July 2020
(This article belongs to the Special Issue Benefits of Dietary Phytochemicals)
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. View Full-Text
Keywords: asaronic acid; diabetes; glucose; interleukin-4; M2 macrophage; mTOR; STAT6 asaronic acid; diabetes; glucose; interleukin-4; M2 macrophage; mTOR; STAT6
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MDPI and ACS Style

Oh, H.; Park, S.-H.; Kang, M.-K.; Kim, Y.-H.; Lee, E.-J.; Kim, D.Y.; Kim, S.-I.; Oh, S.Y.; Na, W.; Lim, S.S.; Kang, Y.-H. 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. Nutrients 2020, 12, 2006. https://doi.org/10.3390/nu12072006

AMA Style

Oh H, Park S-H, Kang M-K, Kim Y-H, Lee E-J, Kim DY, Kim S-I, Oh SY, Na W, Lim SS, Kang Y-H. 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. Nutrients. 2020; 12(7):2006. https://doi.org/10.3390/nu12072006

Chicago/Turabian Style

Oh, Hyeongjoo, Sin-Hye Park, Min-Kyung Kang, Yun-Ho Kim, Eun-Jung Lee, Dong Y. Kim, Soo-Il Kim, Su Y. Oh, Woojin Na, Soon S. Lim, and Young-Hee Kang. 2020. "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" Nutrients 12, no. 7: 2006. https://doi.org/10.3390/nu12072006

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