Predominant role of microglia in brain iron retention in Sanfilippo syndrome, a pediatric neurodegenerative disease

Abstract

Neuroinflammation and iron accumulation are hallmarks of a variety of adult neurodegenerative diseases. In Sanfilippo syndrome (mucopolysaccharidosis type III, MPSIII, a pediatric neurodegenerative disease that shares some features with adult neurodegenerative diseases), the progressive accumulation of heparan sulfate oligosaccharides (HSOs) induces microglia and astrocytes to produce pro-inflammatory cytokines leading to severe neuroinflammation. The objectives of the present study were (1) to measure the local iron concentration and to assess iron metabolism in the brain of a MPSIIIB murine model and (2) to identify the brain cells involved in this accumulation. We found that iron accumulation in MPSIIIB mice primarily affected the cerebral cortex where hepcidin levels were higher than in wild-type mice, and increased with aging. This increase was correlated with low expression of ferroportin 1 (FPN1), and thus brain iron retention. Moreover, we showed in vitro that HSOs are directly responsible for the production of hepcidin and the relative decrease in FPN1 expression when added to cultures of microglia and, to a lesser extent, to cultures of astrocytes. In contrast, no significant differences were observed in neurons. Hepcidin induction results from activation of the TLR4 pathway and STAT3 signaling, and leads to iron retention within microglia. Our results show that microglia have a key role in cerebral hepcidin overexpression and thus in the brain iron accumulation observed in the MPSIIIB model.

Brain iron transport

“…At present, information on the mechanisms involved in iron transport and homeostasis in oligodendrocytes and microglia remains very limited as compared to neurons and astrocytes. In addition, how the expression of iron transport proteins is controlled in the brain under physiological conditions, and the genetic and non‐genetic causes that might lead to misregulation of brain iron metabolism are two key questions that have yet to be answered. A number of studies have provided evidence for the existence of hepcidin in the brain (Wang et al ., ; Wang et al, ; Raha‐Chowdhury et al, ; Pellegrino et al, ; Lu et al, ; Puy et al, ; Vela, ; Wang et al, ). Recent studies have shown that this iron regulatory hormone is also a central player in brain iron homeostasis and has a key role in controlling iron transport in the BBB, and iron uptake and release in astrocytes and neuronal cells (Du et al, , ; Gong et al, ).…”

“…(6) A number of studies have provided evidence for the existence of hepcidin in the brain (Wang et al, 2008a;Wang et al, 2010;Raha-Chowdhury et al, 2015;Pellegrino et al, 2016;Lu et al, 2017;Puy et al, 2018;Vela, 2018;Wang et al, 2019). Recent studies have shown that this iron regulatory hormone is also a central player in brain iron homeostasis and has a key role in controlling iron transport in the BBB, and iron uptake and release in astrocytes and neuronal cells (Du et al, 2011Gong et al, 2016).…”

“…The reduced expression of Fpn1 has also been connected with the activation of N ‐methyl‐D‐aspartate (NMDA) receptor (NR)‐induced iron accumulation and neurodegeneration in dopamine (DA) neurons in Parkinson's disease (Xu et al, ) and brain iron retention in Sanfilippo syndrome, a pediatric neurodegenerative disease (Puy et al, ). Global Heph knockout (Heph KO) has been demonstrated to induce a significant increase in iron levels in the cortex, hippocampus, brain stem and cerebellum in the brain of mice (Jiang et al, ).…”

Regulation of tissue iron homeostasis: the macrophage “ferrostat”

“…Accordingly, iron must be tightly regulated on a cell-to-cell basis to ensure normal homeostatic function. Microglia, the resident Mɸs of the CNS, play an integral role in regulating brain iron levels (102,(104)(105)(106)(107)(108)(109). Microglia express iron transport and storage proteins, including DMT1, TfR, ferritin, Fpn, and hepcidin, and acquire both holo-Tf and NTBI (104,107).…”

“…In addition to neurons, oligodendrocytes and astrocytes also respond to changes in microglial iron-handling phenotype, further highlighting the importance of these cells in regulating overall brain iron homeostasis (115,116). For example, repressing microglial ferritin and hepcidin promotes oligodendrocyte-mediated healing after an ischemic insult (117), and microglial release of iron packaged in FtH under conditions of low parenchymal availability assists in functional oligodendrocyte cell survival (106,107).…”