[9, 10] It should, however, be noted that microglial activation is a continuum that depends on the stimulus encountered in their microenvironment.[11] It has been suggested that

under different pathological conditions, different stimuli act on different microglial receptors to orchestrate microglial 3-MA price response with a shift towards a more deleterious or a more neuroprotective phenotype.[12] The dynamic microglia interacts with different types of cells in the inflammatory environment, both of neural and immune origin. In particular, T cells, a component of the neuroinflammatory reaction in CNS diseases, can modulate microglial activation through secretion of pro-inflammatory and anti-inflammatory cytokines.[13] In this context, interferon-γ (IFN-γ) secreted by T helper type 1 T cells induces a classically activated phenotype in microglia upon binding to the IFN-γ receptors 1/2,[14] with up-regulation of MHC class II and selleck chemicals co-stimulatory molecules and enhancement of their function as antigen-presenting

cells,[13] possibly through microglia–T-cell cross-talk via the CD40–CD40 ligand interaction.[11] In contrast, low doses of IFN-γ or the anti-inflammatory cytokine IL-4, which is released by T helper type 2 cells, promote an alternatively activated profile with a release of neurotrophic factors.[15] In addition to Toll-like receptors (TLR) and other pattern recognition receptors through which they perceive, and react to, the presence of pathogens, microglia express a number of other receptors, whose up- or down-regulation depends on microglial activation status under pathological conditions. In vitro stimulation of mouse microglia with TLR agonists, including lipopolysaccharide (LPS) for TLR4 and CpG DNA for TLR9, leads to increased secretion of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-12, as well as nitric oxide, that in turn Farnesyltransferase cause neuronal injury.[16] Recently, microRNA let-7 was shown to activate microglia, acting as a signalling activator of TLR7.[17] Activation of microglial TLR-signalling

pathway(s) plays a role also in non-infectious CNS diseases, as a response to endogenous danger signals.[16] For example, heat-shock protein 60 released from injured CNS cells binds microglia through TLR4 and triggers neuronal injury in a TLR4-dependent and myeloid differentiation factor 88-dependent manner, inducing release of neurotoxic nitric oxide from microglia.[18] Maintenance of the interaction between CD200 expressed on neurons and its receptor CD200R expressed on microglia is an off signal that is essential for preventing the expression of a classically activated microglial profile with over-activation of microglia and subsequent neurotoxicity.[19] Similarly, disruption of the CX3CL1–CX3CR1 interaction results in highly activated microglia with increased IL-1β production that may induce neurotoxicity.