Microglial reaction induced by noncytotoxic methylmercury treatment leads to neuroprotection via interactions with astrocytes and IL‐6 release

Abstract

Microglial cells react early to a neurotoxic insult. However, the bioactive factors and the cell-cell interactions leading to microglial activation and finally to a neuroprotective or neurodegenerative outcome remain to be elucidated. Therefore, we analyzed the microglial reaction induced by methylmercury (MeHgCl) using cell cultures of different complexity. Isolated microglia were found to be directly activated by MeHgCl (10(-10) to 10(-6) M), as indicated by process retraction, enhanced lectin staining, and cluster formation. An association of MeHgCl-induced microglial clusters with astrocytes and neurons was observed in three-dimensional cultures. Close proximity was found between the clusters of lectin-stained microglia and astrocytes immunostained for glial fibrillary acidic protein (GFAP), which may facilitate interactions between astrocytes and reactive microglia. In contrast, immunoreactivity for microtubule-associated protein (MAP-2), a neuronal marker, was absent in the vicinity of the microglial clusters. Interactions between astrocytes and microglia were studied in cocultures treated for 10 days with MeHgCl. Interleukin-6 release was increased at 10(-7) M of MeHgCl, whereas it was decreased when each of these two cell types was cultured separately. Moreover, addition of IL-6 to three-dimensional brain cell cultures treated with 3 x 10(-7) M of MeHgCl prevented the decrease in immunostaining of the neuronal markers MAP-2 and neurofilament-M. IL-6 administered to three-dimensional cultures in the absence of MeHgCl caused astrogliosis, as indicated by increased GFAP immunoreactivity. Altogether, these results show that microglial cells are directly activated by MeHgCl and that the interaction between activated microglia and astrocytes can increase local IL-6 release, which may cause astrocyte reactivity and neuroprotection.

Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment

“…Further work to determine if the mercury-induced activation of microglia was involved in neuronal apoptosis showed no relationship. With exposure to low levels of mercury, a neuroprotective effect was observed as a result of the microglial reactivity and the induction and release of IL-6 from astrocytes [106,107]. More recent work [108] utilizing a continuous (10 -50 days) application of the heavy metals, lead and mercury, to aggregating brain-cell cultures demonstrated an increase in amyloid precursor protein with lead and the formation of insoluble Aβ by mercury.…”

Activated microglia modulate astroglial enzymes involved in oxidative and inflammatory stress and increase the resistance of astrocytes to oxidative stress in Vitro

“…In many instances it is not understood, why glial activation sometimes has a more protective and in other cases a more detrimental impact on nervous tissue during the course of a neurological disease (Tacconi, 1998). While a moderate release of cyto-and chemokines by activated microglia and their capability of glutamate removal is associated with a neuroprotective effect, a prolonged or excessive activation and a strong release of nitric oxide with successive formation of peroxinitrite is rather connected with a disturbance of neural cell functions (Beckman and Koppenol, 1996;Eskes et al, 2002;Hanisch, 2002;Hanisch and Kettenmann, 2007;Nakajima and Kohsaka, 2004;Streit, 2005). Likewise, the isomorphic type of astrogliosis leads to the release of, e.g.…”

A Microscopic Study of Language-Related Cortex in Autism

“…Many toxins induce gliosis, including metals such as lead, iron andmercury, which specifically induce glial proliferation, degeneration anddecreased cellular function in some regions of the brain [29][30][31][32][33] . Neurotoxicity of metals is primarily mediated by increased oxidative stress and both increased metals and increased oxidative stress are reported in autism [34,35] .…”