Acid sphingomyelinase actively triggers microparticle release from glia cells

CNR Institute of Neuroscience and Department of Medical Pharmacology, University of Milano, Milano, Italy.
The EMBO Journal (Impact Factor: 10.43). 04/2009; 28(8):1043-54. DOI: 10.1038/emboj.2009.45
Source: PubMed


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-1beta, 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 P2X7, microparticle shedding is associated with rapid activation of acid sphingomyelinase, which moves to plasma membrane outer leaflet. ATP-induced shedding and IL-1beta 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-1beta 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-1beta release, thus, opening new strategies for the treatment of neuroinflammatory diseases.

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    • "Microparticles containing ␤-actin are released from vascular endothelial cells stimulated by inflammatory mediators [29] [30] [31] [32]. However, reported released vesicles and microparticles are generally much smaller in size than the cofilin rods seen here in AD brain [29] [30]. Nevertheless, these mechanisms could point to cofilin rods/aggregates as potential markers of microglial activation and/or inflammation. "
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    ABSTRACT: Background: Imaging of human brain as well as cellular and animal models has highlighted a role for the actin cytoskeleton in the development of cell pathology in Alzheimer's disease (AD). Rods and aggregates of the actin-associated protein cofilin are abundant in grey matter of postmortem AD brain and rods are found inside neurites in animal and cell models of AD. Objective: We sought further understanding of the significance of cofilin rods/aggregates to the disease process: Do rods/aggregates correlate with AD progression and the development of hallmark neurofibrillary tangles and neuropil threads? Are cofilin rods/aggregates found in the same neurites as hyperphosphorylated tau? Methods: The specificity of rods/aggregates to AD compared with general aging and their spatial relationship to tau protein was examined in postmortem human hippocampus, inferior temporal cortex, and anterior cingulate cortex. Results: The presence of cofilin rods/aggregates correlated with the extent of tau pathology independent of patient age. Densities of rods/aggregates were fourfold greater in AD compared with aged-matched control brains and rods/aggregates were significantly larger in AD brain. We did not find evidence for our hypothesis that intracellular cofilin rods are localized to tau-positive neuropil threads. Instead, data suggest the involvement of microglia in the clearance of cofilin rods/aggregates and/or in their synthesis in and around amyloid plaques and surrounding neuropil. Conclusion: Cofilin rods and aggregates signify events initiated early in the pathological cascade. Further definition of the mechanisms leading to their formation in the human brain will provide insights into the cellular causes of AD.
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    • "It has been suggested that these micMP may be a rapid and specific way for the brain to relay its immune status to not only its own resident microglial population, but also to the systemic circulation (Bianco et al., 2009). MicMP and astrocytic MP are frequently found to contain IL-1b and have been shown to release it upon stimulation by ATP (Bianco et al., 2009). Since ATP is often associated with neuroinflammation , it is therefore reasonable to assume that the release of ATP from damaged neurons may be a way of rapidly activating microglia and opening MP pores for swift dissemination of IL-1b and other proinflammatory cytokines. "
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