Acid sphingomyelinase activity triggers microparticle release from glial cells

Abstract

We have earlier shown that microglia, the immune cells of the CNS, release microparticles from cell plasma membrane after ATP stimulation. These vesicles contain and release IL-1b, a crucial cytokine in CNS inflammatory events. In this study, we show that microparticles are also released by astrocytes and we get insights into the mechanism of their shedding. We show that, on activation of the ATP receptor P2X 7 , microparticle shedding is associated with rapid activation of acid sphingomyelinase, which moves to plasma membrane outer leaflet. ATPinduced shedding and IL-1b release are markedly reduced by the inhibition of acid sphingomyelinase, and completely blocked in glial cultures from acid sphingomyelinase knockout mice. We also show that p38 MAPK cascade is relevant for the whole process, as specific kinase inhibitors strongly reduce acid sphingomyelinase activation, microparticle shedding and IL-1b release. Our results represent the first demonstration that activation of acid sphingomyelinase is necessary and sufficient for microparticle release from glial cells and define key molecular effectors of microparticle formation and IL-1b release, thus, opening new strategies for the treatment of neuroinflammatory diseases.

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

“…Oxidative stress leads to the activation of sphingomyelinases and ceramide production, which activates p38 MAPK pathway (Chen et al , 2008). In turn, p38 MAPK was shown to activate ASM in glial cells (Bianco et al , 2009). Thus, we hypothesized that the p38 MAPK pathway could be an important player in the activation of the sphingomyelinases and consequent inhibition of Shigella infection, in a context of cellular stress.…”

Regulated Secretion of Acid Sphingomyelinase

“…S1), consistent with previous reports on S-SMase (20,40). This is an important distinction given that aSMase has been suggested to regulate (and be subject to regulation by) other cellular trafficking processes in other cell types, such as release of cytotoxic T-cell granules (modified secretory lysosomes) (54) and microparticle formation in glial cells (55), which involve distinct regulatory mechanisms and may not involve S-SMase specifically. In the future, it will become increasingly important to identify which form of aSMase (S-SMase or L-SMase) is detected at the PM to dissect out the roles (and regulation) of each form of the enzyme.…”

Extracellular-vesicle type of volume transmission and tunnelling-nanotube type of wiring transmission add a new dimension to brain neuro-glial networks

“…Astrocytes can release EMVs by an ATPinduced stimulation of P2X7 receptors followed by an action of acid sphingomyelinase [72]. The astrocytic EMVs move into the extracellular space and carry a large number of transfer compounds such as mitochondria, mitochondrial DNA (mtDNA), ATP, Hsp70, functional glutamate transporters, FGF-2, miRNA, etc.…”