Macrophages sensing oxidized DAMPs reprogram their metabolism to support redox homeostasis and inflammation through a TLR2-Syk-ceramide dependent mechanism.
Macrophages sensing oxidized DAMPs reprogram their metabolism to support redox homeostasis and inflammation through a TLR2-Syk-ceramide dependent mechanism.
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巨噬细胞传感氧化潮湿的潮湿，通过TLR2-Syk-Ceramide依赖机制重新编程其代谢，以支持氧化还原稳态和炎症。
DOI：
10.1016/j.molmet.2017.11.002
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发表时间：
2018-01
影响因子：
8.1
通讯作者：
Leitinger N
中科院分区：
文献类型：
--
作者：
Serbulea V;Upchurch CM;Ahern KW;Bories G;Voigt P;DeWeese DE;Meher AK;Harris TE;Leitinger N
巨噬细胞通过感知和响应环境信号来控制组织稳态和炎症。然而，巨噬细胞对氧化组织损伤的代谢适应及其转化为炎症机制仍然是一个谜。在这里，我们确定了内源性氧化衍生的DAMPs（氧化磷脂，OxPL）在体外诱导的关键调控途径，导致形成独特的氧化氧化调节代谢表型（Mox），这与传统的经典或替代巨噬细胞激活明显不同。出乎意料的是，代谢组学分析表明，Mox严重依赖葡萄糖代谢和戊糖磷酸途径（PPP）来支持GSH的产生和nrf2依赖性抗氧化基因的表达。虽然巨噬细胞对OxPL的代谢适应包括短暂的有氧糖酵解抑制，但它也导致炎症基因表达上调。与经典激活（M1）巨噬细胞相比，Hif1α介导oxpl诱导的Glut1和VEGF的表达，但Il1β的表达是不可缺少的。在机制上，我们发现OxPL通过tlr2依赖性神经酰胺的产生抑制线粒体呼吸，将TCA代谢物重定向到GSH合成。最后，我们发现脾脏酪氨酸激酶（Syk）是一个关键的下游信号介质，将oxpl诱导的效应转化为神经酰胺产生和炎症基因调控。总之，这些数据证明了代谢和生物能量需求，使巨噬细胞能够通过感知OxPL将组织氧化状态转化为抗氧化或炎症反应。因此，靶向巨噬细胞中失调的氧化还原稳态可能会导致治疗慢性炎症的新疗法。与M1和M2相比，Mox巨噬细胞具有独特的代谢，其特征是抑制呼吸和有氧糖酵解。氧化磷脂（OxPL）在巨噬细胞中将葡萄糖代谢和TCA代谢物导向GSH合成。感知OxPL的巨噬细胞通过Hif1α和Nrf2上调一系列基因。OxPL通过tlr2 - syk -神经酰胺机制诱导巨噬细胞炎症基因表达并抑制呼吸。
Macrophages control tissue homeostasis and inflammation by sensing and responding to environmental cues. However, the metabolic adaptation of macrophages to oxidative tissue damage and its translation into inflammatory mechanisms remains enigmatic. Here we identify the critical regulatory pathways that are induced by endogenous oxidation-derived DAMPs (oxidized phospholipids, OxPL) in vitro, leading to formation of a unique redox-regulatory metabolic phenotype (Mox), which is strikingly different from conventional classical or alternative macrophage activation. Unexpectedly, metabolomic analyses demonstrated that Mox heavily rely on glucose metabolism and the pentose phosphate pathway (PPP) to support GSH production and Nrf2-dependent antioxidant gene expression. While the metabolic adaptation of macrophages to OxPL involved transient suppression of aerobic glycolysis, it also led to upregulation of inflammatory gene expression. In contrast to classically activated (M1) macrophages, Hif1α mediated expression of OxPL-induced Glut1 and VEGF but was dispensable for Il1β expression. Mechanistically, we show that OxPL suppress mitochondrial respiration via TLR2-dependent ceramide production, redirecting TCA metabolites to GSH synthesis. Finally, we identify spleen tyrosine kinase (Syk) as a critical downstream signaling mediator that translates OxPL-induced effects into ceramide production and inflammatory gene regulation. Together, these data demonstrate the metabolic and bioenergetic requirements that enable macrophages to translate tissue oxidation status into either antioxidant or inflammatory responses via sensing OxPL. Targeting dysregulated redox homeostasis in macrophages could therefore lead to novel therapies to treat chronic inflammation. Mox macrophages have a unique metabolism compared to M1 and M2, characterized by suppressed respiration and aerobic glycolysis. Oxidized phospholipids (OxPL) redirect glucose metabolism and TCA metabolites to GSH synthesis in macrophages. Macrophages sensing OxPL upregulate sets of genes via Hif1α and Nrf2. OxPL induce inflammatory gene expression and inhibit respiration in macrophages via a TLR2-Syk-ceramide mechanism.
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影响因子：
24
作者：
Capoulade, Romain;Chan, Kwan L.;Tsimikas, Sotirios
通讯作者：
Tsimikas, Sotirios
影响因子：
20.1
作者：
Choi SH;Harkewicz R;Lee JH;Boullier A;Almazan F;Li AC;Witztum JL;Bae YS;Miller YI
通讯作者：
Miller YI
影响因子：
7.4
作者：
Kadl A;Sharma PR;Chen W;Agrawal R;Meher AK;Rudraiah S;Grubbs N;Sharma R;Leitinger N
通讯作者：
Leitinger N
影响因子：
64.8
作者：
Bochkov, VN;Kadl, A;Leitinger, N
通讯作者：
Leitinger, N
影响因子：
4.1
作者：
DARLEYUSMAR, VM;SEVERN, A;ROGERS, M
通讯作者：
ROGERS, M