Some of these factors have been previously reported, such as MCP-1, which is thought to be important, although not the only factor responsible, for macrophage activation and recruitment (Fischer et al., 2008, Groh et al., 2010, Martini et al., 2008, Toews et al., 1998 and Tofaris et al., 2002). In future studies, it will be important to investigate the roles of the other proteins identified in our studies on the inflammatory response. It is interesting to speculate on the advantages of having Schwann cells

coordinate this inflammatory response. The repair that occurs following peripheral nerve injury requires the coordination of multiple processes. At the site of injury, there is a classical wound-healing response, with the recruitment of inflammatory cells and fibroblasts, both of which are important in repairing the physical damage and defending Angiogenesis inhibitor the area from infection. However, the response to this wound has consequences far, sometimes more than a meter, from the initial site of injury and requires a distinct response, including the breakdown and clearance of axons downstream of the cut and

the development of an environment suitable for regeneration. Although this response includes breakdown of the BNB and the influx of inflammatory cells, the major role of these cells is tissue remodeling rather than dealing with tissue trauma and dangers of infection and is thus likely to require distinct signals and control mechanisms (Medzhitov, 2010). This view is corroborated by studies which have shown a distinct role for B cells in nerve regeneration—in that antibodies directed to myelin debris Doxorubicin in vitro are crucial for the efficiency of the clearance process (Vargas et al.,

2010). Our data show that Schwann cells instigate an inflammatory response via the secretion GBA3 of a specific subset of cytokines. Analysis of this response compared to that elicited following trauma or infection may be useful to determine the different inflammatory responses to these distinct triggers. Consistent with these ideas, an important distinction between the Raf-induced inflammatory response and the response following nerve trauma was the lack of a detectable fibroblast response. Following nerve crush or transection, large numbers of fibroblasts are found in the nerve. Moreover, as the nerve regenerates, fibroblasts are involved in tissue restructuring, forming compartmentalized units called minifascicles, which are thought to provide a protected microenvironment for the regrowing axons (Figure 8B; Morris et al., 1972). The lack of a detectable fibroblast response in the P0-RafTR nerves argues that Raf-mediated Schwann cell signals are not involved in controlling the behavior of these fibroblasts during the repair process. Consistent with this, we find that large numbers of fibroblasts tend to be restricted to the wound site (Parrinello et al., 2010), suggesting that signals associated with the damaged tissue are mediating this response.