Abstract
BackgroundAs the primary immune cells of the central nervous system, microglia contribute to development, homeostasis, and plasticity of the central nervous system, in addition to their well characterized roles in the foreign body and inflammatory responses. Increasingly, inappropriate activation of microglia is being reported as a component of inflammation in neurodegenerative and neuropsychiatric disorders. The statin class of cholesterol-lowering drugs have been observed to have anti-inflammatory and protective effects in both neurodegenerative diseases and ischemic stroke, and are suggested to act by attenuating microglial activity.ResultsWe sought to investigate the effects of simvastatin treatment on the secretory profile and phagocytic activity of primary cultured rat microglia, and to dissect the mechanism of action of simvastatin on microglial activity. Simvastatin treatment altered the release of cytokines and trophic factors from microglia, including interleukin-1-β, tumour necrosis factor-α, and brain derived neurotrophic factor in a cholesterol-dependent manner. Conversely, simvastatin inhibited phagocytosis in microglia in a cholesterol-independent manner.ConclusionsThe disparity in cholesterol dependence of cytokine release and phagocytosis suggests the two effects occur through distinct molecular mechanisms. These two pathways may provide an opportunity for further refinement of pharmacotherapies for neuroinflammatory, neurodegenerative, and neuropsychiatric disorders.
Highlights
As the primary immune cells of the central nervous system, microglia contribute to development, homeostasis, and plasticity of the central nervous system, in addition to their well characterized roles in the foreign body and inflammatory responses
While statins were characterized for their inhibition of cholesterol biosynthesis and lowering of blood cholesterol levels, subsequent mechanistic studies have suggested much of their action in reducing risks for cardiovascular disease are unrelated to cholesterol levels, relating rather to pleiotropic effects including isoprenoid biosynthesis and subsequent protein prenylation [22,23]
We demonstrate for the first time that simvastatin treatment inhibits microglial phagocytosis and alters the release of inflammatory mediators and growth factors via two independent and separable molecular mechanisms
Summary
As the primary immune cells of the central nervous system, microglia contribute to development, homeostasis, and plasticity of the central nervous system, in addition to their well characterized roles in the foreign body and inflammatory responses. Microglia exhibit a spectrum of behaviours including initiation of the inflammatory response, migration, proliferation, and phagocytosis of foreign particles and cellular debris, and modulation of the microenvironment through synthesis and release of trophic and toxic effectors. These curious cells are, far from quiescent in their ‘resting,’ ramified, or surveilling state, playing roles in development and maintenance of the CNS including population control of neuronal precursor cells, The statin class of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been one of the most widely prescribed and successful classes of drugs of all time. We demonstrate for the first time that simvastatin treatment inhibits microglial phagocytosis and alters the release of inflammatory mediators and growth factors via two independent and separable molecular mechanisms
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