, 2006). Therefore, enhancing innate immune responses by Hsp70 induction and the

subsequent activation of TLR2/4 could have beneficial effects on MS and EAE diseases and advocate for the positive role of the innate immunity in this context. High-mobility group box-1 (HMGB-1) is another endogenous TLR2/4 ligand (Maroso et al., 2010), which seems to play an important role in amplifying the immune response in EAE and MS (Andersson et al., 2008). Autologous hematopoietic stem cell transplantation, buy BMS-777607 a radical approach to target the immune system, has shown great benefits in humans (Burt et al., 2009). The beneficial effects of such a strategy depend on check details the formation of a novel tolerant immune system and/or the long-lasting depletion of immunoreactive T cells (Gosselin and Rivest, 2011) (Figure 5). The role played by the innate immune system in brain homeostasis and diseases is becoming one of the most studied subjects in neuroscience. We and many other groups have unraveled important mechanistic insights, although

much remains to be done to understand how it can be modulated to fight against chronic diseases and help the recovery after injuries. Circulating monocytes are now considered a very important target since they act on the surface of the NVU to clear toxic proteins, such as soluble Aβ, within the cerebrovascular system. In doing so, they eliminate critical elements involved in the etiology of Alzheimer’s disease and new data suggest that novel TLR4 ligands can be used as therapeutic approaches to stimulate monocytes and other cells of the NVU (Michaud et al., 2013).

The NVU is also critically involved in the etiology of MS. The inflammatory response taking place in the CNS has often been associated with progressive neuronal damage and chronic Rolziracetam brain diseases. However, accumulating evidence now suggests that CNS-resident microglia and circulating monocytes may have more beneficial effects for neurons than previously thought. It appears likely that monocytic cells and the molecules they produce contribute to tissue repair and neuronal survival/regeneration in certain conditions but become detrimental in other situations. The apparent discrepancies between the harmful and beneficial effects of monocytic cells may be due, at least in part, to the differences in the manner and timing of their activation and in the way they interact with other cells of the NVU. Indeed, monocytic cells and other immune cells produce a different repertoire of cytokines, growth factors, proteases, free radicals, and other molecules depending on the cell subset involved and their state of activation that act not only on neurons but also in every cell of the NVU.