An attenuated immune response by Schwann cells and macrophages inhibits nerve regeneration in aged rats

Although peripheral nerves are capable of regeneration, advanced age decreases the potential for functional recovery after injury. The cellular mechanisms for this are not currently understood. Here, we performed sciatic nerve grafting with young (2 months old) and aged (18 months old) Brown-Norway male rats, in which 1 cm nerve grafts from young or aged rats were sutured into nerves of young or aged rats. Axons were allowed to regenerate until the nerve grafts and distal nerves were harvested at 1, 3, and 7 days and 2 and 6 weeks. At 6 weeks, our data suggested that young nerve grafts supported regeneration better than aged nerve grafts. In addition, myelin debris clearance was inhibited in young nerves when grafted into aged rats, but clearance was faster when aged nerves were grafted into young rats. Further analysis revealed that aged macrophages have delayed migration into injured nerve, and macrophages and Schwann cells from aged rats were less phagocytic for myelin debris in vitro. To understand these impairments, expression levels of pro- and anti-inflammatory cytokines were analyzed at 1 day after injury. Based on these levels, there was not a clear polarization to either an M1 or M2 phenotype; however, expression levels of IL-6, IL-10, CCL2 (MCP1), and Arg-1 were decreased in aged nerves. Taken together, both macrophages and Schwann cells had attenuated responses to nerve injury in aged rats, leading to inefficient clearance of debris and impaired axonal regeneration.