Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions.
Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions.
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DOI：
10.1371/journal.pbio.1002202
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发表时间：
2015-07
期刊：
影响因子：
9.8
通讯作者：
Mauro C
中科院分区：
文献类型：
--
作者：
Haas R;Smith J;Rocher-Ros V;Nadkarni S;Montero-Melendez T;D'Acquisto F;Bland EJ;Bombardieri M;Pitzalis C;Perretti M;Marelli-Berg FM;Mauro C
乳酸长期以来被认为是细胞代谢的“废物”副产品，它在炎症部位积累。最近的研究发现乳酸盐在细胞信号传导中是一种活跃的代谢物，尽管它在炎症期间对免疫细胞的影响在很大程度上尚未被探索。在这里，我们询问乳酸是否负责T细胞留在炎症部位，在那里它们使慢性炎症过程永久化。我们发现乳酸在类风湿性关节炎患者的滑膜中积累。细胞外乳酸钠和乳酸分别抑制CD4+和CD8+ T细胞的运动。这种对T细胞运动的选择性控制是通过亚型特异性转运蛋白（Slc5a12和Slc16a1）介导的，我们发现它们分别由CD4+和CD8+亚群选择性表达。我们在体外和体内进一步证明，乳酸钠介导的对CD4+ T细胞运动的抑制是由于趋化因子受体CXCR3与趋化因子CXCL10结合时激活的糖酵解受到干扰。相反，我们发现乳酸对CD8+ T细胞运动的影响独立于糖酵解控制。在CD4+ T辅助细胞中，乳酸钠也诱导Th17亚群的转换，产生大量的促炎细胞因子IL-17，而在CD8+ T细胞中，乳酸导致其细胞溶解功能的丧失。我们进一步表明，乳酸转运蛋白的表达与类风湿关节炎患者滑膜的临床T细胞评分相关。最后，在腹膜炎的体内模型中，药物或抗体介导的阻断T细胞上亚型特异性乳酸转运蛋白导致其从炎症部位释放。通过建立乳酸在控制促炎T细胞运动和效应功能中的新作用，我们的研究结果提供了驱动慢性炎症的炎症部位T细胞捕获和功能改变的潜在分子机制，并为慢性炎症疾病的治疗提供了靶向治疗干预措施。在慢性炎症部位积累的高水平乳酸可引发浸润性T细胞的不利反应；降低T细胞对乳酸盐的敏感性可能为慢性炎性疾病提供治疗方案。酸性是炎症部位（如关节炎滑膜、动脉粥样硬化斑块和肿瘤微环境）的特征，部分原因是缺氧条件下糖酵解产物乳酸的积累。最近有研究表明，乳酸可能不仅仅是一个旁观者，而且可能调节免疫炎症反应。在这里，我们报告了这样的活性：乳酸通过干扰T细胞迁移所需的糖酵解来抑制T细胞的运动，它导致T细胞产生更多的促炎细胞因子IL-17，并引发细胞溶解活性的丧失。这些现象是T细胞在慢性炎症浸润中的标志性特征。功能改变依赖于不同T细胞亚群特异性乳酸转运蛋白的表达，即CD4+ T细胞中的乳酸钠转运蛋白Slc5a12和CD8+ T细胞中的乳酸转运蛋白Slc16a1。我们认为进入炎症部位的T细胞通过其特定的转运体感知高浓度的乳酸。运动能力的丧失导致它们被困在这个部位，通过它们增加炎症细胞因子的产生而降低细胞溶解能力，它们增加了慢性炎症的有害影响。靶向T细胞上的乳酸转运蛋白和/或代谢途径可能为治疗广泛存在的慢性炎症性疾病提供新的、宝贵的治疗方法。
Lactate has long been considered a “waste” by-product of cell metabolism, and it accumulates at sites of inflammation. Recent findings have identified lactate as an active metabolite in cell signalling, although its effects on immune cells during inflammation are largely unexplored. Here we ask whether lactate is responsible for T cells remaining entrapped in inflammatory sites, where they perpetuate the chronic inflammatory process. We show that lactate accumulates in the synovia of rheumatoid arthritis patients. Extracellular sodium lactate and lactic acid inhibit the motility of CD4+ and CD8+ T cells, respectively. This selective control of T cell motility is mediated via subtype-specific transporters (Slc5a12 and Slc16a1) that we find selectively expressed by CD4+ and CD8+ subsets, respectively. We further show both in vitro and in vivo that the sodium lactate-mediated inhibition of CD4+ T cell motility is due to an interference with glycolysis activated upon engagement of the chemokine receptor CXCR3 with the chemokine CXCL10. In contrast, we find the lactic acid effect on CD8+ T cell motility to be independent of glycolysis control. In CD4+ T helper cells, sodium lactate also induces a switch towards the Th17 subset that produces large amounts of the proinflammatory cytokine IL-17, whereas in CD8+ T cells, lactic acid causes the loss of their cytolytic function. We further show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of rheumatoid arthritis patients. Finally, pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in an in vivo model of peritonitis. By establishing a novel role of lactate in control of proinflammatory T cell motility and effector functions, our findings provide a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders. High levels of lactate that accumulate in chronic inflammatory sites can trigger unfavorable responses in infiltrating T cells; reducing T cells' sensitivity to lactate might offer therapeutic solutions to chronic inflammatory disorders. Acidity is a feature of inflammatory sites such as arthritic synovia, atherosclerotic plaques, and tumor microenvironments and results in part from the accumulation of lactate as a product of glycolysis under hypoxic conditions. Recently it has emerged that lactate may be more than just a bystander and might act to modulate the immune-inflammatory response. Here we report just such activity: lactate inhibits T cell motility by interfering with glycolysis that is required for T cells to migrate, it causes T cells to produce higher amounts of the proinflammatory cytokine IL-17, and it triggers loss of cytolytic activity. These phenomena are hallmark features of T cells in chronic inflammatory infiltrates. The functional changes depend on the expression of specific lactate transporters by different subsets of T cells, namely the sodium lactate transporter Slc5a12 in CD4+ T cells and the lactic acid transporter Slc16a1 in CD8+ T cells. We propose that T cells entering inflammatory sites sense high concentrations of lactate via their specific transporters. Loss of motility leads to their entrapment at the site, where through their increased production of inflammatory cytokines yet decreased cytolytic capacity, they add detrimentally to chronic inflammation. Targeting lactate transporters and/or metabolic pathways on T cells could deliver novel, invaluable therapeutics for the treatment of widespread chronic inflammatory disorders.