Network Integration of Parallel Metabolic and Transcriptional Data Reveals Metabolic Modules that Regulate Macrophage Polarization

被引：1550

作者：

Jha, Abhishek K. ^{[1
]}

Huang, Stanley Ching-Cheng ^{[2
]}

Sergushichev, Alexey ^{[2
,3
]}

Lampropoulou, Vicky ^{[2
]}

Ivanova, Yulia ^{[2
]}

Loginicheva, Ekaterina ^{[2
]}

Chmielewski, Karina ^{[1
]}

Stewart, Kelly M. ^{[1
]}

Ashall, Juliet ^{[2
]}

Everts, Bart ^{[2
]}

Pearce, Edward J. ^{[2
]}

Driggers, Edward M. ^{[1
]}

Artyomov, Maxim N. ^{[2
]}

机构：

[1] Agios Pharmaceut, Cambridge, MA 02139 USA

[2] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA

[3] ITMO Univ, St Petersburg 197101, Russia

来源：

IMMUNITY | 2015年 / 42卷 / 03期

关键词：

NITRIC-OXIDE; GLYCOSYLATION; IMMUNITY; INNATE;

D O I：

10.1016/j.immuni.2015.02.005

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. 13 C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes.

引用

页码：419 / 430

页数：12

共 39 条

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