Saitoh Shinichi, Takeda Yuji, Araki Akemi, Nouchi Yusuke, Yamaguchi Risako, Nakajima Osamu, Asao Hironobu
Department of Immunology, Faculty of Medicine, Yamagata University, Yamagata, 990-9585, Japan.
Research Center for Molecular Genetics, Institute for Promotion of Medical Science Research, Yamagata University, Yamagata, 990-9585, Japan.
Inflammation. 2024 Dec 19. doi: 10.1007/s10753-024-02212-1.
5-aminolevulinic acid (5-ALA) is an amino acid essential for the synthesis of heme, which is important for various cellular functions, including the mitochondrial electron transport chain. We previously established heterozygous knockout mice (Alas1) for 5-ALA synthase 1 (ALAS1), the rate-limiting enzyme for 5-ALA synthesis, and reported that the mice developed non-obese insulin-resistant diabetes. In the present study, we used these mice to analyze the role of 5-ALA in the immune system. Using a lipopolysaccharide (LPS)-induced septic shock model, Alas1 mice showed reduced mortality compared to wild-type (WT) mice. In this model experiment, the plasma concentration of inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), and the chemokine monocyte chemoattractant protein-1 (MCP1) decreased in Alas1 mice compared that in WT mice, and inflammatory cell infiltration into the peritoneal cavity was also decreased. In ex vivo experiments, exogenous 5-ALA pretreatment enhanced LPS-induced TNFα and IL-6 production from peripheral blood leukocytes of Alas1 mice. Additionally, 5-ALA pretreatment enhanced LPS-induced activation of inflammatory cytokine genes in innate immune cells. Interestingly, the phagocytosis and reactive oxygen species (ROS) producing abilities of neutrophils were clearly hampered in Alas1 mice compared to WT mice, but after 2 weeks of 5-ALA administration to Alas1 mice, both abilities were significantly recovered up to the level in WT mice. These results reveal that 5-ALA is essential for the function of innate immune cells. Because 5-ALA can be supplemented orally, it has the potential to be used as a drug to restore innate immune function.
5-氨基酮戊酸（5-ALA）是血红素合成所必需的氨基酸，血红素对包括线粒体电子传递链在内的各种细胞功能都很重要。我们之前建立了5-ALA合成限速酶5-ALA合酶1（ALAS1）的杂合敲除小鼠（Alas1），并报道这些小鼠患非肥胖胰岛素抵抗性糖尿病。在本研究中，我们利用这些小鼠分析5-ALA在免疫系统中的作用。在脂多糖（LPS）诱导的脓毒症休克模型中，与野生型（WT）小鼠相比，Alas1小鼠的死亡率降低。在该模型实验中，与WT小鼠相比，Alas1小鼠血浆中肿瘤坏死因子α（TNFα）和白细胞介素-6（IL-6）等炎性细胞因子以及趋化因子单核细胞趋化蛋白-1（MCP1）的浓度降低，并且炎性细胞向腹腔的浸润也减少。在体外实验中，外源性5-ALA预处理增强了LPS诱导的Alas1小鼠外周血白细胞产生TNFα和IL-6的能力。此外，5-ALA预处理增强了LPS诱导的天然免疫细胞中炎性细胞因子基因的激活。有趣的是，与WT小鼠相比，Alas1小鼠中性粒细胞的吞噬作用和产生活性氧（ROS）的能力明显受到阻碍，但在给Alas1小鼠施用5-ALA 2周后，这两种能力均显著恢复至WT小鼠的水平。这些结果表明，5-ALA对天然免疫细胞的功能至关重要。由于5-ALA可以口服补充，它有潜力用作恢复天然免疫功能的药物。
