RESUMEN
Microglia are immune cells of the central nervous system and are implicated in brain inflammation. However, how brain microglia modulate transport and metabolism of the essential metal iron in response to pro- and anti-inflammatory environmental cues is unclear. Here, we characterized uptake of transferrin (Tf)-bound iron (TBI) and non-Tf-bound iron (NTBI) by immortalized microglial (IMG) cells. We found that these cells preferentially take up NTBI in response to the proinflammatory stimulus lipopolysaccharide (LPS) or ß-amyloid (Aß). In contrast, the anti-inflammatory cytokine interleukin 4 (IL-4) promoted TBI uptake. Concordant with these functional data, levels of the Tf receptor (TfR) in IMG cells were up-regulated in response to IL-4, whereas divalent metal transporter-1 (DMT1) and ferritin levels increased in response to LPS or Aß. Similar changes in expression were confirmed in isolated primary adult mouse microglia treated with pro- or anti-inflammatory inducers. LPS-induced changes in IMG cell iron metabolism were accompanied by notable metabolic changes, including increased glycolysis and decreased oxidative respiration. Under these conditions, the extracellular acidification rate was increased, compatible with changes in the cellular microenvironment that would support the pH-dependent function of DMT1. Moreover, LPS increased heme oxygenase-1 (HO1) expression in IMG cells, and iron released because of HO1 activity increased the intracellular labile free-iron pool. Together, this evidence indicates that brain microglia preferentially acquire iron from Tf or from non-Tf sources, depending on their polarization state; that NTBI uptake is enhanced by the proinflammatory response; and that under these conditions microglia sequester both extra- and intracellular iron.
Asunto(s)
Proteínas de Transporte de Catión/genética , Hierro/metabolismo , Microglía/metabolismo , Receptores de Transferrina/genética , Transferrina/genética , Péptidos beta-Amiloides/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Proteínas de Transporte de Catión/metabolismo , Línea Celular Transformada , Microambiente Celular , Ferritinas/genética , Ferritinas/metabolismo , Regulación de la Expresión Génica , Glucólisis/efectos de los fármacos , Glucólisis/genética , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Concentración de Iones de Hidrógeno , Inflamación , Transporte Iónico , Lipopolisacáridos/farmacología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Microglía/efectos de los fármacos , Microglía/patología , Fosforilación Oxidativa/efectos de los fármacos , Cultivo Primario de Células , Receptores de Transferrina/metabolismo , Transducción de Señal , Transferrina/metabolismoRESUMEN
Iron homeostasis is an essential prerequisite for metabolic and neurological functions throughout the healthy human life, with a dynamic interplay between intracellular and systemic iron metabolism. The development of different neurodegenerative diseases is associated with alterations of the intracellular transport of iron and heavy metals, principally mediated by Divalent Metal Transporter 1 (DMT1), responsible for Non-Transferrin Bound Iron transport (NTBI). In addition, DMT1 regulation and its compartmentalization in specific brain regions play important roles during aging. This review highlights the contribution of DMT1 to the physiological exchange and distribution of body iron and heavy metals during aging and neurodegenerative diseases. DMT1 also mediates the crosstalk between central nervous system and peripheral tissues, by systemic diffusion through the Blood Brain Barrier (BBB), with the involvement of peripheral iron homeostasis in association with inflammation. In conclusion, a survey about the role of DMT1 and iron will illustrate the complex panel of interrelationship with aging, neurodegeneration and neuroinflammation.