Taurine Antagonizes Macrophages M1 Polarization by Mitophagy-Glycolysis Switch Blockage via Dragging SAM-PP2Ac Transmethylation.

Ling Meng,Ning Zhang,Chunhua Lan,Qihui Wang,Xia Zeng,Cailing Lu,Li Lan,Xinhang Wang,Xiyi Li,Shen Tang,Laiming Mo,Bin Wu,Chengying Chen

doi:10.3389/fimmu.2021.648913

Abstract

The excessive M1 polarization of macrophages drives the occurrence and development of inflammatory diseases. The reprogramming of macrophages from M1 to M2 can be achieved by targeting metabolic events. Taurine promotes for the balance of energy metabolism and the repair of inflammatory injury, preventing chronic diseases and complications. However, little is known about the mechanisms underlying the action of taurine modulating the macrophage polarization phenotype. In this study, we constructed a low-dose LPS/IFN-γ-induced M1 polarization model to simulate a low-grade pro-inflammatory process. Our results indicate that the taurine transporter TauT/SlC6A6 is upregulated at the transcriptional level during M1 macrophage polarization. The nutrient uptake signal on the membrane supports the high abundance of taurine in macrophages after taurine supplementation, which weakens the status of methionine metabolism, resulting in insufficient S-adenosylmethionine (SAM). The low availability of SAM is directly sensed by LCMT-1 and PME-1, hindering PP2Ac methylation. PP2Ac methylation was found to be necessary for M1 polarization, including the positive regulation of VDAC1 and PINK1. Furthermore, its activation was found to promote the elimination of mitochondria by macrophages via the mitophagy pathway for metabolic adaptation. Mechanistically, taurine inhibits SAM-dependent PP2Ac methylation to block PINK1-mediated mitophagy flux, thereby maintaining a high mitochondrial density, which ultimately hinders the conversion of energy metabolism to glycolysis required for M1. Our findings reveal a novel mechanism of taurine-coupled M1 macrophage energy metabolism, providing novel insights into the occurrence and prevention of low-grade inflammation, and propose that the sensing of taurine and SAM availability may allow communication to inflammatory response in macrophages.

Highlights

Inflammation is an innate host defense mechanism used to fight infections and various types of tissue damage
THP-1 cells were treated with PMA (100 nmol/L) for 24 h to activate M0 macrophages, and challenged with LPS (10 ng/mL) and IFN-g (20 ng/mL) for 48 h to induce the polarization of M0 to M1 pro-inflammatory macrophages (Figure 1A)
Maintaining PP2Ac Methylation by ABL127 Blocks the Mitophagy-Mediated Metabolic Reprogramming of Taurine Our results showed that taurine maintained mitochondrial density by inhibiting mitophagy, adaptively reducing the level of glycolysis and downregulating the M1 polarization level, as PP2Ac methylation

Summary

Introduction

Inflammation is an innate host defense mechanism used to fight infections and various types of tissue damage. Macrophages have a high degree of heterogeneity and plasticity. They are polarized into different phenotypes during the infection process: the classic activated M1 type and the alternatively activated M2 type, which coordinate pro-inflammatory and anti-inflammatory repairs during infection to maintain homeostasis [3, 4]. Pro-inflammatory M1 macrophages activated by IFN-g and Toll-like receptors (TLRs) rely on enhanced aerobic glycolysis initiated by rapid glucose uptake [5]. This rapid and direct energy supply is conducive for macrophages to produce inflammatory factors, which have an anti-infection effect [6]. The regulation of energy metabolism represents a viable means for the treatment of inflammatory diseases

Methods

Results

Conclusion