Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal1. In various pathophysiological conditions, however, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity2,3. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kupffer cells, and depend on Csf1 and Nrf2. The spleen likewise recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages due to the suppressive action of Csf2. Inhibiting monocyte recruitment to the liver leads to kidney and liver damage. These observations identify the liver as the primary organ supporting rapid erythrocyte removal and iron recycling and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.

Metformin is sometimes proposed to be an “anti-aging” drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for type 2 diabetics. Large prospective, placebo-controlled trials are planned, in pilot stage or running, to find a new use (or indication) for an aging population. As one of the metformin trials has “frailty” as its endpoint, similar to a trial with a plant-derived senolytic, the latter class of novel anti-aging drugs is briefly discussed. Concerns exist not only for vitamin B₁₂ and B₆ deficiencies, but also about whether there are adverse effects of metformin on individuals who try to remain healthy by maintaining cardiovascular fitness via exercise.

Iron is essential for many biological functions including neurotransmitter synthesis, where the metal is a co-factor of tyrosine hydroxylase, which converts tyrosine to dopamine and further to norepinephrine. As the shared chemical structure, called catechol, may potentially bind iron we questioned whether tyrosine derived hormones would impact on cellular iron homeostasis in macrophages, which are central for the maintenance of body iron homeostasis. Using murine bone marrow-derived macrophages (BMDMs), we investigated the effect of catecholamines and found that only dopamine but neither tyrosine, nor norepinephrine, affected cellular iron homeostasis. Exposure of macrophages to dopamine increased the uptake of non-transferrin bound iron into cells. The expansion of intracellular iron upon dopamine treatment resulted in oxidative stress responses as evidenced by increased expression of nuclear factor erythroid 2-related factor (Nrf2) and hypoxia inducible factor-1α. As a consequence, the transcriptional expression of stress response genes such as heme oxygenase-1 and the iron export protein ferroportin1 were significantly increased. Genetic deletion of Nrf2 abolished these effects of dopamine. Dopamine directly affects cellular iron homeostasis by increasing iron incorporation into macrophages and subsequently promoting intracellular oxidative stress responses. Our observations are of interest for disorders involving dopamine and iron dyshomeostasis such as Parkinson's disease and restless legs syndrome, partly enlightening the underlying pathology or the therapeutic efficacy of dopamine agonists to overcome neuronal iron deficiency.

No abstract

No abstract