Inflammatory Mediators of Axon Regeneration in the Central and Peripheral Nervous Systems

Abstract

Although most pathways in the mature central nervous system cannot regenerate when injured, research beginning in the late 20th century has led to discoveries that may help reverse this situation. Here, we highlight research in recent years from our laboratory identifying oncomodulin (Ocm), stromal cell-derived factor (SDF)-1, and chemokine CCL5 as growth factors expressed by cells of the innate immune system that promote axon regeneration in the injured optic nerve and elsewhere in the central and peripheral nervous systems. We also review the role of ArmC10, a newly discovered Ocm receptor, in mediating many of these effects, and the synergy between inflammation-derived growth factors and complementary strategies to promote regeneration, including deleting genes encoding cell-intrinsic suppressors of axon growth, manipulating transcription factors that suppress or promote the expression of growth-related genes, and manipulating cell-extrinsic suppressors of axon growth. In some cases, combinatorial strategies have led to unprecedented levels of nerve regeneration. The identification of some similar mechanisms in human neurons offers hope that key discoveries made in animal models may eventually lead to treatments to improve outcomes after neurological damage in patients.

Calcium-Associated Proteins in Neuroregeneration

“…Generally, the central nervous systemand peripheral nervous system exhibit distinct abilities in terms of nerve regeneration. While, in the PNS, axon regeneration can occur spontaneously, in the CNS, after injury, such a process is inhibited by many extrinsic and intrinsic factors [103][104][105]. Moreover, itsintrinsic regenerative ability is self-limiting, depending on the characteristics and type of injury.…”

“…The initiation of nerve regeneration involves a rapid influx of sodium and calcium ions, triggering essential cellular processes. CaMKII emerges as a central coordinator in Ca 2+ signal transduction, activating various protein kinase pathways and transcription factors, including CREB [105,124].…”

“…OCM's impact on peripheral sensory neurons, similar to the optic nerve, is intricately linked to SDF1. Their combined application efficiently expedites the regeneration of both peripheral nerve and spinal cord axons [105].…”