5-Aminolevulinic Acid (5-ALA) Plays an Important Role in the Function of Innate Immune Cells.

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.