Cytokine toxicity to oligodendrocyte precursors is mediated by iron

Abstract

Inflammatory processes play a key role in the pathogenesis of a number of common neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Abnormal iron accumulation is frequently noted in these diseases and compelling evidence exists that iron is involved in inflammatory reactions. Histochemical stains for iron repeatedly demonstrate that oligodendrocytes, under normal conditions, stain more prominently than any other cell type in the brain. Therefore, we examined the hypothesis that cytokine toxicity to oligodendrocytes is iron mediated. Oligodendrocytes in culture were exposed to interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha). Toxicity was observed in a dose-dependent manner for IFN-gamma and TNF-alpha. IL-1beta was not toxic in the concentrations used in this study. The toxic concentration of IFN-gamma, and TNF-alpha was lower if the cells were iron loaded, but iron loading had no effect on the toxicity of IL-1beta. These data provide insight into the controversy regarding the toxicity of cytokines to oligodendrocytes by revealing that iron status of these cells will significantly impact the outcome of cytokine treatment. The exposure of oligodendrocytes to cytokines plus iron decreased mitochondrial membrane potential but activation of caspase 3 is limited. The antioxidant, TPPB, which targets mitochondria, protected the oligodendrocytes from the iron-mediated cytotoxicity, providing further support that mitochondrial dysfunction may underlie the iron-mediated cytokine toxicity. Therapeutic strategies involving anti-inflammatory agents have met with limited success in the treatment of demyelinating disorders. A better understanding of these agents and the contribution of cellular iron status to cytokine toxicity may help develop a more consistent intervention strategy.

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

“…12,31 In the present study, we confirmed that exposure to low concentrations of TNF-a (10 ng/ml) impairs OPC differentiation, causing an accumulation of early progenitors and reducing the relative amounts of differentiating oligodendrocytes in vitro. This phenomenon was not accompanied by a significant induction of apoptosis, which occurred only when the TNF-a concentration was increased to 100 ng/ml.…”

“…After 7 days of culture, the OPCs were treated for 24 h with a sublethal concentration of TNF-a, or 10 ng/ml, as suggested in a previous study. 12 Subsequently, the growth factors present within the medium, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) (which are fundamental to OPC proliferation), were replaced by the thyroid hormone triiodothyronine (T3) to stimulate cell differentiation. After 5 days, the cells were fixed and immunostained for markers of different stages of oligodendrocyte maturation.…”

Cellular iron status influences the functional relationship between microglia and oligodendrocytes

“…The concentration of DFO was also selected to compare to our earlier studies on astrocytes (Robb and Connor, 1998). Calcein, an iron-sensitive dye, was used to determine that the amount of TMHF and DFO used in this study was sufficient to affect the labile iron pool (Zhang et al, 2005).…”

Iron and Iron Regulatory Proteins in Amoeboid Microglial Cells Are Linked to Oligodendrocyte Death in Hypoxic Neonatal Rat Periventricular White Matter through Production of Proinflammatory Cytokines and Reactive Oxygen/Nitrogen Species

“…In addition to ROS, activated microglia secrete cytokines such as TNF-␣ and IL-1␤ that can induce the apoptosis of oligodendrocytes (Zhang et al, 2005;Deng et al, 2008). We have shown that, under hypoxic conditions, iron mediates the release of proinflammatory cytokines TNF-␣ and IL-1␤.…”