Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring
Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring
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DOI：
10.1016/j.cmet.2019.10.004
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发表时间：
2019-12-03
期刊：
影响因子：
29
通讯作者：
Mauro, Claudio
中科院分区：
文献类型：
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作者：
Pucino, Valentina;Certo, Michelangelo;Mauro, Claudio
乳酸在组织微环境中的积聚是炎症性疾病和癌症的一个特征。在这里，我们在慢性炎症的背景下评估免疫细胞对乳酸的反应。我们报道，炎症组织中乳酸的积累有助于人类CD4(+)T细胞上调乳酸转运体SLC5A12。SLC5A12介导的乳酸摄取到CD4(+)T细胞诱导其效应表型的重塑，导致通过核PKM2/STAT3增加IL17的产生和促进脂肪酸的合成。由于糖酵解减少和脂肪酸合成增强，它还导致发炎组织中的CD4(+)T细胞滞留。此外，抗体介导的SLC5A12阻断可以改善关节炎小鼠模型的疾病严重程度。最后，我们认为乳酸/SLC5A12诱导的代谢重编程是类风湿关节炎患者淋巴滑膜炎的一个显著特征，也是慢性炎症性疾病的潜在治疗靶点。
Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4(+) T cells. SLC5A12-mediated lactate uptake into CD4(+) T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4(+) T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.