IL-6 promotes regeneration and functional recovery after cortical spinal tract injury by reactivating intrinsic growth program of neurons and enhancing synapse formation

Most neurons in adult mammalian central nervous system (CNS) fail to regenerate their axons after injury. Peripherally conditioned primary sensory neurons have an increased capacity to regenerate their central processes. Recent studies demonstrate that a conditioning lesion increased intrinsic growth capability is associated with the up-regulation of a group of growth-associated genes, one of the most established is interleukin-6 (IL-6). However, the cellular and molecular mechanisms by which IL-6 exerts its beneficial effect on axonal regeneration and functional recovery remain to be elucidated. The purpose of this study is to further investigate the molecular mechanisms of IL-6 in promoting regeneration and functional recovery after spinal cord injury (SCI). Here, we demonstrate that in vitro administration of IL-6 enhances neurite outgrowth of neurons on an inhibitory substrate myelin proteins, accompanied by increased expression of growth-associated genes GAP-43, SPRR1A and Arginase I. In vivo, intrathecal delivery of IL-6 for 7 days after cortical spinal tract injury induces synaptic rearrangements of sprouting axons and increases the expression of mTOR in neurons surrounding the lesion site, accompanied by improved functional recovery. In conclusion, our results show that IL-6 increases the expression of growth-associated genes and induces the expression of mTOR in lesion adjacent neurons, resulting in reactivating the intrinsic growth program of neurons to promote axonal regrowth and functional recovery after SCI.

► IL-6 enhanced neurite outgrowth of neurons on an inhibitory substrate in vitro.
► IL-6 upregulated the expression of GAP-43, SPRR1A and Arginase I in vitro.
► IL-6 promoted axonal sprouting, synapse formation and function recovery in vivo.
► IL-6 increased expression of mTOR in neurons while decreased in astrocytes in vivo.
► IL-6 induced the expression of pSTAT3 in neurons around lesion site in vivo.