Achieving CNS axon regeneration by manipulating convergent neuro-immune signaling

Abstract

After central nervous system (CNS) trauma, axons have a low capacity for regeneration. Regeneration failure is associated with a muted regenerative response of the neuron itself, combined with a growth-inhibitory and cytotoxic post-injury environment. After spinal cord injury (SCI), resident and infiltrating immune cells (especially microglia/macrophages) contribute significantly to the growth-refractory milieu near the lesion. By targeting both the regenerative potential of the axon and the cytotoxic phenotype of microglia/macrophages, we may be able to improve CNS repair after SCI. In this review, we discuss molecules shown to impact CNS repair by affecting both immune cells and neurons. Specifically, we provide examples of pattern recognition receptors, integrins, cytokines/chemokines, nuclear receptors and galectins that could improve CNS repair. In many cases, signaling by these molecules is complex and may have contradictory effects on recovery depending on the cell types involved or the model studied. Despite this caveat, deciphering convergent signaling pathways on immune cells (which affect axon growth indirectly) and neurons (direct effects on axon growth) could improve repair and recovery after SCI. Future studies must continue to consider how regenerative therapies targeting neurons impact other cells in the pathological CNS. By identifying molecules that simultaneously improve axon regenerative capacity and drive the protective, growth-promoting phenotype of immune cells, we may discover SCI therapies that act synergistically to improve CNS repair and functional recovery.

Fig. 1

depicts the localization of factors and receptors that elicit convergent signaling in cells of the immune and nervous systems

Fig. 2.

CNS repair-related processes can be initiated or prevented via similar pathways/receptors in both macrophages and neurons. These factors can alter neuron extrinsic (e.g., macrophages) and intrinsic responses to improve or hamper repair. Some factors have reparative effects on both macrophage phenotype and neuron growth/survival (e.g., TLR2, RXR heterodimers, Gal3), whereas others have contradictory effects on the two cell types (e.g., α_Vβ₃ integrin, IL-6, CXCL12-CXCR4). Factors discussed are placed on a continuum of CNS repair, from beneficial (top) to harmful (bottom) (placements are estimates based on known effects). “+” represents a beneficial effect; “-” represents a harmful effect. See text for references.