Metabolic reprogramming of the myeloid lineage by Schistosoma mansoni infection persists independently of antigen exposure.
Metabolic reprogramming of the myeloid lineage by Schistosoma mansoni infection persists independently of antigen exposure.
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曼氏血吸虫感染引起的髓系代谢重编程与抗原暴露无关
DOI：
10.1371/journal.ppat.1009198
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发表时间：
2021-01
期刊：
影响因子：
6.7
通讯作者：
Fairfax KC
中科院分区：
文献类型：
--
作者：
Cortes-Selva D;Gibbs L;Maschek JA;Nascimento M;Van Ry T;Cox JE;Amiel E;Fairfax KC
巨噬细胞在代谢性疾病和胆固醇代谢的发病机制中具有确定的作用，其中巨噬细胞的替代性活化被认为在高脂肪饮食诱导的疾病期间对葡萄糖和胆固醇代谢都有益。蠕虫感染可以保护机体免受代谢性疾病的侵害，但其保护机制尚不清楚。在这里，我们研究了曼氏血吸虫感染和细胞因子激活的骨髓来源的巨噬细胞的代谢特征的影响，使用的方法，整合转录组学，代谢组学和脂质组学在代谢性疾病易感小鼠模型。我们证明，骨髓源性巨噬细胞（BMDM）从S。与未感染的小鼠相比，感染mansoni的雄性ApoE-/-小鼠的线粒体呼吸显著增加。这种变化与穿梭进入TCA循环中间体的葡萄糖和棕榈酸盐增加、游离脂肪酸积累增加以及细胞胆固醇酯、甘油三酯和甘油二酯积累减少相关，并且依赖于mgII活性。全身注射IL-4复合物不能重现全身葡萄糖AUC的降低或感染雄性中观察到的BMDM线粒体呼吸的重新编程。重要的是，雄性骨髓细胞的代谢重编程可通过骨髓移植转移到未感染的宿主，表明在不存在持续抗原暴露的情况下维持重编程。最后，血吸虫诱导的代谢和骨髓调节具有性别依赖性，感染可以保护雄性小鼠，但不能保护雌性小鼠免受葡萄糖耐受不良和肥胖的影响。我们的研究结果确定了蠕虫感染对巨噬细胞代谢特征的可转移的，持久的性别依赖性重编程，为调节蠕虫感染在代谢疾病中的有益作用的因素提供了关键的机制见解。在全球范围内，蠕虫流行地区的代谢性疾病发病率较低。特别是血吸虫病已被证明可以保护雄性小鼠免受动脉粥样硬化，糖尿病和肥胖症的发展，同时改变肝脏巨噬细胞的代谢。在这项研究中，我们试图了解代谢调节是否发生全身性。我们第一次发现，从受感染的雄性小鼠的骨髓髓系祖细胞产生的巨噬细胞在其基础脂质代谢中具有长寿命的增加。我们还发现2型极化细胞因子IL-4不足以复制感染诱导的代谢重编程。重要的是，我们证明了雄性巨噬细胞代谢的变化可以转移到未感染的宿主。这表明代谢重编程是长期存在的，而不暴露于活动性感染，并在骨髓细胞中形成记忆样表型。
Macrophages have a defined role in the pathogenesis of metabolic disease and cholesterol metabolism where alternative activation of macrophages is thought to be beneficial to both glucose and cholesterol metabolism during high fat diet induced disease. It is well established that helminth infection protects from metabolic disease, but the mechanisms underlying protection are not well understood. Here, we investigated the effects of Schistosoma mansoni infection and cytokine activation in the metabolic signatures of bone marrow derived macrophages using an approach that integrated transcriptomics, metabolomics, and lipidomics in a metabolic disease prone mouse model. We demonstrate that bone marrow derived macrophages (BMDM) from S. mansoni infected male ApoE-/- mice have dramatically increased mitochondrial respiration compared to those from uninfected mice. This change is associated with increased glucose and palmitate shuttling into TCA cycle intermediates, increased accumulation of free fatty acids, and decreased accumulation of cellular cholesterol esters, tri and diglycerides, and is dependent on mgll activity. Systemic injection of IL-4 complexes is unable to recapitulate either reductions in systemic glucose AUC or the re-programing of BMDM mitochondrial respiration seen in infected males. Importantly, the metabolic reprogramming of male myeloid cells is transferrable via bone marrow transplantation to an uninfected host, indicating maintenance of reprogramming in the absence of sustained antigen exposure. Finally, schistosome induced metabolic and bone marrow modulation is sex-dependent, with infection protecting male, but not female mice from glucose intolerance and obesity. Our findings identify a transferable, long-lasting sex-dependent reprograming of the metabolic signature of macrophages by helminth infection, providing key mechanistic insight into the factors regulating the beneficial roles of helminth infection in metabolic disease. Globally, helminth endemic regions have lower incidences of metabolic disease. Schistosomiasis in particular has been shown to protect male mice from the development of atherosclerosis, diabetes and obesity while altering the metabolism of liver macrophages. In this study we sought to understand if metabolic modulation occurs systemically. We have found for the first time that macrophages generated from bone marrow myeloid progenitors from infected male mice have long-lived increases in their basal metabolism of lipids. We have also found the type-2 polarizing cytokine IL-4 is not sufficient to replicate infection induced metabolic reprogramming. Importantly, we demonstrate that the changes to male macrophage metabolism can be transferred to an uninfected host. This suggests that metabolic reprogramming is long-lived without exposure to active infection, and develops a memory-like phenotype in myeloid cells.
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DOI：
10.1074/jbc.ra118.001921
发表时间：
2018-04-13
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Carroll RG;Zasłona Z;Galván-Peña S;Koppe EL;Sévin DC;Angiari S;Triantafilou M;Triantafilou K;Modis LK;O'Neill LA
通讯作者：
O'Neill LA
影响因子：
6.7
作者：
Girgis NM;Gundra UM;Ward LN;Cabrera M;Frevert U;Loke P
通讯作者：
Loke P
影响因子：
6.5
作者：
Douglass, John D.;Zhou, Yin Xiu;Storch, Judith
通讯作者：
Storch, Judith
影响因子：
5.4
作者：
Barron, Luke;Wynn, Thomas A.
通讯作者：
Wynn, Thomas A.
影响因子：
64.5
作者：
Adolfsson, J;Månsson, R;Jacobsen, SEW
通讯作者：
Jacobsen, SEW