All three members are expressed in the brain, with higher levels detected for LGP2 and RIG-1 by real-time PCR (Lech et al., 2010). There is much still to learn regarding the role of RLRs in the brain, but both RIG-1 and MDA5 were shown to be implicated in the response to vesicular stomatitis

virus (Furr et al., 2008), the West Nile virus (Daffis et al., 2008), and others. Both MDA5 and RIG-1 are expressed mostly by microglia and astrocytes (Chauhan et al., 2010) but also by neurons in which they contribute to the innate immune response to pathogens (Peltier et al., 2010). The engagement of PRRs converges on NF-κB and/or IRF3 to induce the expression of cytokines (IL-1β, IL-6, TNFα, IL-18, IL-12, IFNβ, TGFβ, etc.), chemokines (MIP-1α, MCP-1, RANTES, etc.), reactive oxygen species (ROS), and free radicals. Describing the effects and roles Gemcitabine mw of each cytokine is beyond the scope of this Review, BMN 673 purchase as excellent Reviews on the subject can be found in the literature (Jaerve and Müller, 2012; Bellavance and Rivest, 2012; Akiyama et al., 2000). For

the purpose of this Review, we will discuss two major cytokines with radically different purposes: IL-1β and TGFβ. IL-1β is a powerful proinflammatory cytokine produced in response to TLR activation in a Myd88-dependent manner, playing a key role in the early stages of innate immune reaction (Herx et al., 2000). After TLR activation and NF-κB induction, IL-1β is produced at the NVU by microglia, cerebral endothelial

cells, and astrocytes (Soulet and Rivest, 2008b) as an inactive protein that is proteolytically processed by the inflammasome to generate its active form (John et al., 2005). IL-1β binds and activates its receptor complex formed by IL-1 receptor type I (IL-1RI) and IL-1RI accessory protein (IL-1RAP) (Steinman, 2013), leading to NF-κB and activating protein-1 (AP-1) nuclear translocation and higher intracellular calcium concentration (Spörri et al., 2001). IL-1RI is present on the surface of cerebral endothelial cells, astrocytes, neurons, and microglia (Srinivasan et al., 2004; Van Dam et al., 1996). Recently, through an isoform of the IL-1RAP specific to the CNS was discovered, further defining the link between inflammation and neuronal survival (Smith et al., 2009). For decades, research on IL-1β has focused on its detrimental effects in neuroinflammation (Friedlander et al., 1997). Recent studies reported new protective and regenerative functions of this cytokine in several CNS disease models, by mainly enhancing the production of insulin-like growth factor-1, ciliary neurotrophic factor, and NGF by astrocytes and microglia (Mason et al., 2001; Herx et al., 2000; DeKosky et al., 1996). In parallel, IL-1β signaling seems to have a major role in BBB functions, as it has been shown to modulate BBB physical permeability and potentially enhanced immune cell infiltration into CNS (Argaw et al., 2006).