Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
Department I of Internal Medicine, University of Cologne, D-50937 Cologne, Germany.
Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16551-16560. doi: 10.1073/pnas.1904885116. Epub 2019 Jul 26.
The dynamic interplay between metabolism and immune responses in health and disease, by which different immune cells impact on metabolic processes, are being increasingly appreciated. However, the potential of master regulators of metabolism to control innate immunity are less understood. Here, we studied the cross-talk between leptin signaling and macrophage function in the context of bacterial infections. We found that upon infection with Gram-negative pathogens, such as Typhimurium, leptin receptor (Lepr) expression increased in both mouse and human macrophages. Unexpectedly, both genetic ablation in macrophages and global pharmacologic leptin antagonization augmented lysosomal functions, reduced Typhimurium burden, and diminished inflammation in vitro and in vivo. Mechanistically, we show that leptin induction activates the mTORC2/Akt pathway and subsequently down-regulates Phlpp1 phosphatase, allowing for phosphorylated Akt to impair lysosomal-mediated pathogen clearance. These data highlight a link between leptin signaling, the mTORC2/Phlpp1/Akt axis, and lysosomal activity in macrophages and have important therapeutic implications for modulating innate immunity to combat Gram-negative bacterial infections.
在健康和疾病中，代谢和免疫反应之间存在动态相互作用，不同的免疫细胞会影响代谢过程，这一点越来越受到重视。然而，代谢的主要调节剂控制先天免疫的潜力还不太了解。在这里，我们研究了瘦素信号与巨噬细胞功能在细菌感染背景下的相互作用。我们发现，在感染革兰氏阴性病原体（如鼠伤寒沙门氏菌）时，小鼠和人巨噬细胞中的瘦素受体（Lepr）表达增加。出乎意料的是，巨噬细胞中的基因缺失和全身性瘦素拮抗都增强了溶酶体功能，减少了鼠伤寒沙门氏菌的负担，并在体外和体内减轻了炎症。从机制上讲，我们表明瘦素诱导激活了 mTORC2/Akt 途径，随后下调了 Phlpp1 磷酸酶，使磷酸化 Akt 能够损害溶酶体介导的病原体清除。这些数据强调了瘦素信号、mTORC2/Phlpp1/Akt 轴与巨噬细胞溶酶体活性之间的联系，并对调节先天免疫以对抗革兰氏阴性细菌感染具有重要的治疗意义。
