Cassiaside C Inhibits M1 Polarization of Macrophages by Downregulating Glycolysis.

Ye Jin Kim,Hyein Woo,Jonghwa Jin,Keun-Gyu Park,Sungwoo Lee,Yeon-Kyung Choi

doi:10.3390/ijms23031696

Abstract

Classically activated M1 macrophages reprogram their metabolism towards enhanced glycolysis to obtain energy and produce pro-inflammatory cytokines after activation by mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor (HIF)-1α. Thus, a strategy that constrains M1 polarization of macrophages via downregulation of glycolysis is essential for treating chronic inflammatory diseases. Cassiae semen has pharmacological activity against various inflammatory diseases. However, it is unclear whether specific compounds within Cassia seeds affect M1 polarization of macrophages. Here, we investigated whether Cassiaside C napthopyrone from Cassiae semen inhibits M1 polarization by downregulating glycolysis. We found that Cassiaside C reduced expression of inducible nitric oxide synthase and cyclooxygenase-2 and the phosphorylation of nuclear factor kappa B, all of which are upregulated in lipopolysaccharide (LPS)/interferon (IFN)-γ-treated Raw264.7 cells and peritoneal macrophages. Moreover, Cassiaside C-treated macrophages showed marked suppression of LPS/IFN-γ-induced HIF-1α, pyruvate dehydrogenase kinase 1, and lactate dehydrogenase A expression, along with downregulation of the phosphoinositide 3-kinases (PI3K)/AKT/mTORC1 signaling pathway. Consequently, Cassiaside C attenuated enhanced glycolysis and lactate production, but rescued diminished oxidative phosphorylation, in M1 polarized macrophages. Thus, Cassiaside C dampens M1 polarization of macrophages by downregulating glycolysis, which could be exploited as a therapeutic strategy for chronic inflammatory conditions.

Highlights

Glycolysis provides cells with a very rapid supply of energy to support biosynthesis; increased glycolysis is a key feature of proliferating cells, including cancer cells, vascular smooth muscles cells, and immune cells [1,2,3]
Consistent with the downregulation of hypoxia-inducible factor (HIF)-1α, pyruvate dehydrogenase kinase 1 (PDK1), and lactate dehydrogenase A (LDHA), we found that Cassiaside C suppressed glycolysis and the glycolytic capacity of LPS/IFN-γ-stimulated peritoneal macrophages, as assessed by measuring the extracellular acidification rate (ECAR) (Figure 4A–D)
The results suggest that the antiinflammatory efficacy of Cassiaside C is attributable to suppression of phosphoinositide 3-kinases (PI3K)/AKT/Mammalian target of rapamycin complex 1 (mTORC1) signaling in LPS/IFN-γ-stimulated macrophages

Summary

Introduction

Glycolysis provides cells with a very rapid supply of energy to support biosynthesis; increased glycolysis is a key feature of proliferating cells, including cancer cells, vascular smooth muscles cells, and immune cells [1,2,3]. Immune cells, such as neutrophils, macrophages, and T lymphocytes, rely heavily on glycolysis to generate cellular adenosine triphosphate (ATP) and biosynthetic precursors and for redox buffering capacity, all of which ensure adequate function and development [4,5,6,7]. Manipulating mTORC1 activity and macrophage polarization has therapeutic potential for chronic inflammatory disease [15]

Methods

Results

Conclusion