Microglia trigger astrocyte-mediated neuroprotection via purinergic gliotransmission

Abstract

Microglia are highly sensitive to even small changes in the brain environment, such as invasion of non-hazardous toxicants or the presymptomatic state of diseases. However, the physiological or pathophysiological consequences of their responses remain unknown. Here, we report that cultured microglia sense low concentrations of the neurotoxicant methylmercury (MeHglow) and provide neuroprotection against MeHg, for which astrocytes are also required. When exposed to MeHglow, microglia exocytosed ATP via p38 MAPK- and vesicular nucleotide transporter (VNUT)-dependent mechanisms. Astrocytes responded to the microglia-derived ATP via P2Y1 receptors and released interleukin-6 (IL-6), thereby protecting neurons against MeHglow. These neuroprotective actions were also observed in organotypic hippocampal slices from wild-type mice, but not in slices prepared from VNUT knockout or P2Y1 receptor knockout mice. These findings suggest that microglia sense and respond to even non-hazardous toxicants such as MeHglow and change their phenotype into a neuroprotective one, for which astrocytic support is required.

Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling

“…In these cells, ATP is stored in dense-cored vesicles [65][66][67], secretory lysosomes [68,69], or non-characterized vesicular compartments [70][71][72]. Consistently, VNUT is reported to be associated with intracellular vesicles in astrocytes and microglia [71][72][73][74][75]. Secretory lysosomes have recently been identified as dual functional organelles that serve as both a degradative and as secretory compartments [76].…”

Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain

“…ATP is primarily released from neurons, astrocytes, and microglia via VNUTmediated exocytosis (12,(25)(26)(27)(28). Previous studies have demonstrated that depolarization-dependent ATP release from neurons is inhibited by tetanus neurotoxin or the cell-permeable Ca 2+ chelator EGTA-tetraacetoxymethyl ester (AM), both of which are known inhibitors of exocytosis (25).…”

P2Y1 Receptor Activation of the TRPV4 Ion Channel Enhances Purinergic Signaling in Satellite Glial Cells

“…ATP stimulates P2Y 1 receptor-dependent glutamate release from astrocytes, thereby increasing neuronal excitability (69). Activated microglia can also release ATP, triggering astrocyte-mediated modulation of excitatory neurotransmission and neuroprotective effects via P2Y 1 (70,71). Within sensory ganglia, P2X 7 , P2Y 1 , P2Y 2 , and P2Y 12 receptors have been identified in SGCs (19,26,27).…”