Cellular iron status influences the functional relationship between microglia and oligodendrocytes

Abstract

Previously, we have reported that there is a spatiotemporal relationship between iron accumulation in microglia and oligodendrocytes during normal development and in remyelination following injury. This in vivo observation has prompted us to develop a cell culture model to test the relationship between iron status of microglia and survival of oligodendrocytes. We found that conditioned media from iron-loaded microglia increases the survival of oligodendrocytes; but conditioned media from iron loaded activated microglia is toxic to oligodendrocytes. In the trophic condition, one of the proteins released by iron-loaded microglia is H-ferritin, and transfecting the microglia with siRNA for H-ferritin blocks the trophic response on oligodendrocytes. Lipopolysaccharide (LPS) activation decreases the amount of H-ferritin that is released from microglia and increases the release of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. LPS activation of iron-enriched microglia results in the activation of NF-kB and greater release of cytokines when compared with that of control microglia; whereas treating microglia with an iron chelator is associated with less NF-kB activation and less release of cytokines. These results indicate that microglia play an important role in iron homoeostasis and that their iron status can influence how microglia influence growth and survival of oligodendrocytes. The results further indicate that ferritin, released by microglia, is a significant source of iron for oligodendrocytes.

Ceruloplasmin Protects Injured Spinal Cord from Iron-Mediated Oxidative Damage

“…This is supported by the evidence that wild-type mice treated with the iron chelator, starting the day after contusion injury, exhibit improvement in locomotor recovery between 3 and 6 weeks after injury that coincides with the period when iron staining is reduced in these macrophages. We cannot rule out the possibility that some of the iron that comes out of these macrophages is safely bound to secreted ferritin (Zhang et al, 2006). Our results with the chelator suggest that at least some of the released iron is redox active and chelatable, which is consistent with reports studying iron release from macrophages after erythrophagocytosis (Moura et al, 1998;Knutson et al, 2005).…”

Cellular and subcellular localizations of nonheme ferric and ferrous iron in the rat brain: a light and electron microscopic study by the perfusion-Perls and -Turnbull methods

“…In the developing brain, microglia provides ferritin as a trophic factor to oligodendrocytes for myelination (Zhang et al, 2006). In our results, in sporadic occurrence throughouts the brain, a small number of resting microglia and phagocytic microglia were heavily filled with Fe(III)-and Fe(II)-deposits throughout the cell body and processes where lysosomes and the cytosol were strongly stained.…”

Oligodendrocyte Fate after Spinal Cord Injury

“…A follow-up study revealed that OPC proliferation and OL genesis occurring in response to intraspinal microglia activation was significantly reduced by iron chelation, revealing that available iron is necessary for a maximal pro-oligogenic response of microglial activation [35]. This is in accordance with in vitro evidence showing that the iron status of microglia affects their functional relationship with OPCs [36]. In addition, recent work by our group revealed that OPCs internalize macrophage-derived ferritin both in vivo and in vitro, suggesting ferritin may serve as a pro-oligogenic signal between macrophages and OPCs (Schonberg and McTigue, personal observation).…”