Regulated necrosis orchestrates microglial cell death in manganese- induced toxicity

PORTE ALCÓN SOLEDAD; GOROJOD ROXANA MAYRA; KOTLER MÓNICA LIDIA

NEUROSCIENCE

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2018 vol. 393 p. 206 - 225

0306-4522

Microglia, the brain resident immune cells, play prominentroles in immune surveillance, tissue repair and neural regeneration.Despite these pro-survival actions, the relevance of these cells in theprogression of several neuropathologies has been established. In thecontext of manganese (Mn) overexposure, it has been proposed thatmicroglial activation contributes to enhance the neurotoxicity. However,the occurrence of a direct cytotoxic effect of Mn on microglial cellsremains controversial. In the present work, we investigated the potentialvulnerability of immortalized mouse microglial cells (BV-2) towards Mn2+,focusing on the signalling pathways involved in cell death. Evidenceobtained showed that Mn2+ induces a decrease in cell viability which isassociated with reactive oxygen species (ROS) generation. In this reportwe demonstrated, for the first time, that Mn2+ triggers regulatednecrosis (RN) in BV-2 cells involving two central mechanisms: parthanatosand lysosomal disruption. The occurrence of parthanatos is supported byseveral cellular and molecular events: i) DNA damage; ii) AIFtranslocation from mitochondria to the nucleus; iii) mitochondrialmembrane permeabilization; and iv) PARP1- dependent cell death. On theother hand, Mn2+ induces lysosomal membrane permeabilization (LMP) andcathepsin D (CatD) release into the cytosol supporting the lysosomaldisruption. Pre-incubation with CatB and D inhibitors partially preventedthe Mn2+- induced cell viability decrease. Altogether these events pointto lysosomes as players in the execution of RN. In summary, our resultssuggest that microglial cells could be direct targets of Mn2+ damage. Inthis scenario, Mn2+ triggers cell death involving RN pathways.