2015年3月20日訊 /生物谷BIOON/ --近日，來自美國華盛頓大學的研究人員在著名國際免疫學期刊immunity發表封面文章，他們發現了調節巨噬細胞極化的新代謝機制，為開發調控免疫細胞代謝的藥物提供了新的可能性。
巨噬細胞的一個關鍵特性就是其能夠根據環境因子不同，向不同方向極化形成不同類型的巨噬細胞。巨噬細胞極化常伴隨著轉錄和代謝水平的變化，它的激活能夠顯著改變一些基因的表達以及部分化合物濃度。但直到最近，人們對於巨噬細胞激活帶來的變化仍只是了解一部分，仍不能全面解析。
為研究巨噬細胞極化，研究人員在RNA測序和對代謝物的高通量質譜檢測基礎上開發了一種檢測代謝產物變化的非靶向分析方法。通過結合生化反應網絡數據，研究人員最終發現了一系列能夠揭示巨噬細胞極化相關代謝機制的化學反應。基於這些信息，科學家們確定了最可能的代謝途徑，並利用同位素標記實驗和藥物抑制實驗證明了這些途徑確實對於巨噬細胞極化具有重要作用。
綜上所述，這些發現對於開發調控免疫細胞代謝，發揮促炎或抗炎作用的藥物具有重要提示，該項研究首次大規模地詳細描述了巨噬細胞極化過程中的生化反應和信號通路，具有重要意義。（生物谷Bioon.com）
Network Integration of Parallel Metabolic and Transcriptional Data Reveals Metabolic Modules that Regulate Macrophage Polarization
Abhishek K. Jha, Stanley Ching-Cheng Huang, Alexey Sergushichev, Vicky Lampropoulou, Yulia Ivanova, Ekaterina Loginicheva, Karina Chmielewski, Kelly M. Stewart, Juliet Ashall, Bart Everts5, Edward J. Pearce4, Edward M. Driggers46correspondenceemail, Maxim N. Artyomov
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. 13C-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.