Division of Critical Care, Department of Pediatrics, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201.
Division of Pulmonary & Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201.
Immunohorizons. 2020 May 15;4(5):245-258. doi: 10.4049/immunohorizons.2000015.
Sepsis is the leading cause of death in the world. Recent reports suggest that in response to sepsis, metabolism of macrophages switches from oxidative phosphorylation to aerobic glycolysis. MAPK phosphatase (MKP)-1 (also known as DUSP1) localized in the nucleus and preferentially dephosphorylates p38 and JNK. MKP-1 controls the expression of numerous inflammatory genes and transcription factors, thereby regulating innate and adaptive immunity. MKP-1-deficient animals exhibit aberrant metabolic responses following bacterial infections with a markedly increased mortality in response to sepsis. Because metabolic reprogramming modulates immune responses to TLR-4 activation, we investigated the effect of MKP-1 deficiency on mitochondrial electron transport chains involved in oxidative phosphorylation and transcription factors regulating mitochondrial biogenesis. Mitochondrial biogenesis is regulated by three nuclear-encoded proteins, including transcription factor A (TFAM), nuclear respiratory factors (NRF-1), and peroxisome proliferator-activated receptor γ coactivator-1-α (PGC-1α). We show that MKP-1-deficient mice/macrophages exhibit, at baseline, higher expression of oxidative phosphorylation, TFAM, PGC-1α, and NRF-1 associated with increased respiration and production of reactive oxygen species as compared with wild-type mice. Surprisingly, MKP-1-deficient mice/macrophages responded to sepsis or LPS with an impaired metabolic switch; despite enhanced glycolysis, a preserved mitochondrial function and biogenesis are exhibited. Furthermore, inhibition of p38 MAPK had no significant effect on TFAM and NRF-1 either in MKP-1-deficient macrophages or in wild-type macrophages. These findings support the conclusion that MKP-1 plays an important role in regulating proteins involved in glycolysis and oxidative phosphorylation and modulates expression of mitochondrial transcription factors.
脓毒症是世界上主要的死亡原因。最近的报告表明，为了应对脓毒症，巨噬细胞的代谢从氧化磷酸化转变为有氧糖酵解。MAPK 磷酸酶 (MKP)-1（也称为 DUSP1）定位于细胞核中，优先使 p38 和 JNK 去磷酸化。MKP-1 控制着众多炎症基因和转录因子的表达，从而调节先天和适应性免疫。MKP-1 缺陷动物在细菌感染后表现出异常的代谢反应，对脓毒症的死亡率明显增加。由于代谢重编程调节 TLR-4 激活后的免疫反应，我们研究了 MKP-1 缺陷对参与氧化磷酸化的线粒体电子传递链和调节线粒体生物发生的转录因子的影响。线粒体生物发生受三种核编码蛋白调节，包括转录因子 A (TFAM)、核呼吸因子 (NRF-1) 和过氧化物酶体增殖物激活受体 γ 共激活因子 1-α (PGC-1α)。我们表明，MKP-1 缺陷型小鼠/巨噬细胞在基础状态下表现出更高的氧化磷酸化、TFAM、PGC-1α 和 NRF-1 的表达，与野生型小鼠相比，呼吸作用和活性氧的产生增加。令人惊讶的是，MKP-1 缺陷型小鼠/巨噬细胞对脓毒症或 LPS 的代谢转换反应受损；尽管糖酵解增强，但仍表现出线粒体功能和生物发生的保留。此外，在 MKP-1 缺陷型巨噬细胞或野生型巨噬细胞中，抑制 p38 MAPK 对 TFAM 和 NRF-1 均没有显著影响。这些发现支持了 MKP-1 在调节糖酵解和氧化磷酸化相关蛋白以及调节线粒体转录因子表达中发挥重要作用的结论。
