Extracellular Acidity Reprograms Macrophage Metabolism and Innate Responsiveness.
Extracellular Acidity Reprograms Macrophage Metabolism and Innate Responsiveness.
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细胞外酸度重新编程巨噬细胞代谢和先天反应性
DOI：
10.4049/jimmunol.2100014
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发表时间：
2021-06-15
期刊：
影响因子：
--
通讯作者：
Lu M
中科院分区：
文献类型：
--
作者：
Jiang W;Le J;Wang PY;Cheng X;Smelkinson M;Dong W;Yang C;Chu Y;Hwang PM;Munford RS;Lu M
低pH值可增加巨噬细胞中线粒体的生物合成和功能。低pHe诱导M2样极化，降低免疫反应性。当恢复正常pH值时，这些变化是可逆的。虽然器官功能减退和免疫抑制是严重脓毒症的危及生命的特征，但如果患者存活，功能减退的器官和免疫细胞通常会恢复正常功能。由于组织间质液在脓毒症反应期间可变为酸性，因此我们检验了低细胞外pH值（pHe）可诱导C57 BL/6 J小鼠腹腔巨噬细胞可逆性代谢和功能变化的假设。与正常pH培养的巨噬细胞相比，生活在酸性介质中的巨噬细胞使用较少的葡萄糖和外源性脂肪酸来产生ATP。乳酸、谷氨酰胺和从头合成的脂肪酸支持线粒体产生ATP，从而获得更大的质量、最大耗氧率和备用呼吸能力。细胞转变为M2样状态，对LPS的免疫反应改变，吞噬能力略有下降，但当中性pH恢复时，它们恢复了基础能量产生，正常线粒体功能和促炎反应。低pHe诱导支持巨噬细胞存活的变化，同时使细胞更少促炎（更“耐受”）和更少吞噬细菌的能力。巨噬细胞对低间质pH值的反应可能导致许多脓毒症患者中观察到的可逆性器官功能减退和免疫麻痹。
Key Points Low pHe increases mitochondrial biogenesis and function in macrophages. Low pHe induces M2-like polarization, reducing immune responsiveness. These changes are reversible when normal pH is restored. Visual Abstract Although organ hypofunction and immunosuppression are life-threatening features of severe sepsis, the hypofunctioning organs and immune cells usually regain normal functionality if patients survive. Because tissue interstitial fluid can become acidic during the septic response, we tested the hypothesis that low extracellular pH (pHe) can induce reversible metabolic and functional changes in peritoneal macrophages from C57BL/6J mice. When compared with macrophages cultured at normal pHe, macrophages living in an acidic medium used less glucose and exogenous fatty acid to produce ATP. Lactate, glutamine, and de novo–synthesized fatty acids supported ATP production by mitochondria that gained greater mass, maximal oxygen consumption rate, and spare respiratory capacity. The cells transitioned to an M2-like state, with altered immune responses to LPS and slightly decreased phagocytic ability, yet they regained basal energy production, normal mitochondrial function, and proinflammatory responsiveness when neutral pHe was restored. Low pHe induces changes that support macrophage survival while rendering the cells less proinflammatory (more “tolerant”) and less able to phagocytose bacteria. Macrophage responses to low interstitial pH may contribute to the reversible organ hypofunction and immunoparalysis noted in many patients with sepsis.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
29
作者：
Corbet, Cyril;Pinto, Adan;Feron, Olivier
通讯作者：
Feron, Olivier
影响因子：
4.4
作者：
Cantó C;Auwerx J
通讯作者：
Auwerx J
影响因子：
64.5
作者：
Faubert B;Li KY;Cai L;Hensley CT;Kim J;Zacharias LG;Yang C;Do QN;Doucette S;Burguete D;Li H;Huet G;Yuan Q;Wigal T;Butt Y;Ni M;Torrealba J;Oliver D;Lenkinski RE;Malloy CR;Wachsmann JW;Young JD;Kernstine K;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
5.5
作者：
BARTH, MW;HENDRZAK, JA;MORAHAN, PS
通讯作者：
MORAHAN, PS