早在1998年，就有研究人員最早發(fā)現(xiàn)間充質(zhì)干細(xì)胞（mesenchymal stem cells， MSCs）具有免疫抑制功能，其在治療自身免疫性疾病中有很好的應(yīng)用前景。此前研究認(rèn)為，MSCs的免疫抑制作用與其所處的炎癥微環(huán)境密切相關(guān)，一方面炎癥因子賦予MSCs免疫抑制功能，另一方面炎癥因子的多樣性及其水平的動(dòng)態(tài)變化又決定MSCs免疫調(diào)節(jié)能力的可塑性。此外，不同微環(huán)境下MSCs的免疫特性和免疫調(diào)節(jié)機(jī)制也是當(dāng)前國(guó)際MSCs治療研究領(lǐng)域的熱點(diǎn)。

近日，來(lái)自中國(guó)科學(xué)院上海營(yíng)養(yǎng)與健康研究所時(shí)玉舫、王瑩課題組系統(tǒng)分析了低氧條件下MSCs的蛋白表達(dá)譜，發(fā)現(xiàn)其分泌的胰島素樣生長(zhǎng)因子-2（insulin like growth factor-2，IGF-2）是治療自身免疫性疾病的重要分子，并揭示了IGF-2執(zhí)行免疫抑制功能的分子機(jī)制及其在對(duì)抗自身免疫性疾病中的應(yīng)用潛能。相關(guān)研究結(jié)果發(fā)表于國(guó)際學(xué)術(shù)期刊Cell Metabolism上。該研究通過(guò)系統(tǒng)比對(duì)不同培養(yǎng)條件下的MSCs對(duì)自身免疫性疾病的治療作用，發(fā)現(xiàn)低氧培養(yǎng)條件下人源MSCs通過(guò)分泌IGF-2有效治療模型動(dòng)物自身反應(yīng)性腦脊髓炎。該作用主要依賴于IGF-2對(duì)于PD-L1巨噬細(xì)胞的促進(jìn)作用，并通過(guò)PD-L1提高Treg的分化，執(zhí)行對(duì)自身免疫性疾病的抑制作用。通過(guò)分析巨噬細(xì)胞，研究人員發(fā)現(xiàn)IGF-2不影響成熟巨噬細(xì)胞向具有抗炎功能巨噬細(xì)胞的轉(zhuǎn)變，而是作用于單核細(xì)胞向巨噬細(xì)胞分化成熟的過(guò)程，使得在IGF-2調(diào)控下成熟的巨噬細(xì)胞具備持續(xù)的免疫抑制能力。這一作用的形成與IGF-2通過(guò)表觀遺傳調(diào)控和代謝重編程使得巨噬細(xì)胞處于對(duì)氧化磷酸化的代謝偏向性密切相關(guān)。此外，阻斷線粒體電子傳遞鏈復(fù)合物V的活性能夠抑制IGF-2重編程巨噬細(xì)胞上PD-L1的高表達(dá)及其促進(jìn)Treg分化的能力。

綜上所述，該研究闡明了低氧條件下MSCs通過(guò)IGF-2賦予成熟過(guò)程中巨噬細(xì)胞的氧化磷酸化代謝偏向性，誘導(dǎo)抗炎巨噬細(xì)胞的形成并促進(jìn)Treg分化，從而有效抑制自身免疫性疾病，為自身免疫性疾病的治療提供了新的策略和效應(yīng)分子。

推薦閱讀原文：

IGF-2 preprograms maturing macrophages to acquire oxidative phosphorylation-dependent anti-inflammatory properties.

Recent investigations revealed that macrophages could be trained with an altered responsiveness, raising the possibility of combating autoimmune diseases by imparting anti-inflammatory capabilities to these cells. While investigating the effect of mesenchymal stem cells on experimental autoimmune encephalomyelitis (EAE), we found a critical role of insulin-like growth factor 2 (IGF-2) in training macrophages to become anti-inflammatory during their maturation. IGF-2 exerts its effects by preprogramming maturing macrophages to commit oxidative phosphorylation (OXPHOS). IGF-2-preprogrammed macrophages maintained the mitochondrial complex V activities even upon pro-inflammation stimulation, thus enabling an elevated programmed death-ligand 1 (PD-L1) expression. PD-L1 neutralization abolished the beneficial effect of IGF-2 on EAE. Furthermore, adoptive transfer of IGF-2-preprogrammed macrophages to EAE mice increased Tregs and alleviated the diseases. Our results demonstrate that shaping macrophage responsiveness by IGF-2 is effective in managing inflammatory diseases, and the OXPHOS commitment can be preset to determine the anti-inflammatory fate of macrophages.