Statins amplify TLR-induced responses in microglia via inhibition of cholesterol biosynthesis

Statins inhibit the endogenous intracellular mevalonate pathway and exposure to statins affects innate and adaptive immune responses. Different statins are currently under evaluation as (co)therapy in neuro-inflammatory diseases like multiple sclerosis. However, there are important discrepancies in the reported effects of statins on innate immune responses in different cell types. Studies to characterize such responses in clinically relevant primary cells are currently lacking. In this study, we investigated the effect of statins on Toll-like receptor (TLR)-induced responses of microglia, the resident macrophages of the central nervous system (CNS). Exposure of primary microglia from adult rhesus monkeys to different statins strongly amplified pro-inflammatory cytokine protein and mRNA levels in response to myeloid differentiation primary response gene 88-dependent TLR activation in particular. Rather than affecting nuclear facor-κB activation levels, statin exposure affected stress-activated protein/Jun-amino-terminal and p38 kinase signaling pathways. Mechanistic studies using specific pathway inhibitors and rescue experiments show that statin-induced inhibition of cholesterol biosynthesis, rather than inhibition of isoprenylation, was mainly responsible for the amplified TLR responses. Additionally, microglia were more sensitive to statin-mediated effects than bone marrow-derived macrophages of the same donor. This correlated to lower intrinsic microglial expression levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the enzyme targeted by statins. Amplification of TLR-induced responses in microglia by statin exposure might contribute to the generation of a more pro-inflammatory CNS microenvironment which can be of relevance for the pathogenesis of neuroinflammatory disorders.