Contribution of Macrophages to Enhanced Regenerative Capacity of Dorsal Root Ganglia Sensory Neurons by Conditioning Injury

Abstract

Although the central branches of the dorsal root ganglion (DRG) sensory neurons do not spontaneously regenerate, a conditioning peripheral injury can promote their regeneration. A potential role of macrophages in axonal regeneration was proposed, but it has not been critically addressed whether macrophages play an essential role in the conditioning injury model. After sciatic nerve injury (SNI) in rats, the number of macrophages in DRGs gradually increased by day 7. The increase persisted up to 28 d and was accompanied by upregulation of inflammatory mediators, including oncomodulin. A macrophage deactivator, minocycline, reduced the macrophage number and expressions of the inflammatory mediators. Molecular signatures of conditioning effects were abrogated by minocycline, and enhanced regenerative capacity was substantially attenuated both in vitro and in vivo. Delayed minocycline infusion abrogated the SNI-induced long-lasting heightened neurite outgrowth potential, indicating a role for macrophages in the maintenance of regenerative capacity. Intraganglionic cAMP injection also resulted in an increase in macrophages, and minocycline abolished the cAMP effect on neurite outgrowth. However, conditioned media (CM) from macrophages treated with cAMP did not exhibit neurite growth-promoting activity. In contrast, CM from neuron-macrophage cocultures treated with cAMP promoted neurite outgrowth greatly, highlighting a requirement for neuron-macrophage interactions for the induction of a proregenerative macrophage phenotype. The growth-promoting activity in the CM was profoundly attenuated by an oncomodulin neutralizing antibody. These results suggest that the neuron-macrophage interactions involved in eliciting a proregenerative phenotype in macrophages may be a novel target to induce long-lasting regenerative processes after axonal injuries in the CNS.

Anti-inflammatory effect of stem cells against spinal cord injury via regulating macrophage polarization

“…66 Cytokines such as IL-10 secreted by M2 macrophages could promote axonal regrowth and functional recovery after SCI. 67 Taken together, M1 macrophages can block axonal regeneration.…”

Inflammation and Optic Nerve Regeneration

“…On the other hand, there is evidence that neutrophils exert a detrimental effect in secondary CNS damage, which occurs at a later stage of immune response (Souza-Rodrigues et al, 2008). In the case of peripheral nerve injury, immune depletion of neutrophils does not affect the ability of dorsal root sensory neurons to regenerate their axons (Nadeau et al, 2011), whereas suppressing the macrophage response strongly suppresses regeneration (Barrette et al, 2008;Kwon et al, 2013). In addition to their presence at the site of nerve damage, macrophages infiltrate dorsal root ganglia after a peripheral nerve lesion, and depletion of these cells specifically at this site suppresses the conditioning lesion effect, that is, the ability of dorsal root ganglion (DRG) neurons to regenerate their centrally directed axon branch through the dorsal root after injury to the peripheral branch.…”

cAMP-responsive Element-binding Protein (CREB) and cAMP Co-regulate Activator Protein 1 (AP1)-dependent Regeneration-associated Gene Expression and Neurite Growth

“…JNK and ERK) that ultimately lead to transcriptional changes at the soma (9, 44 -46). Additionally, perturbation of the normal injury response of macrophages and Schwann cells can occlude axon regeneration and the peripheral lesion conditioning effect (47)(48)(49)(50). Some of these factors, such macrophage-released oncomodulin, work in synergy with cAMP to promote both peripheral nervous system and CNS axon regeneration (50,51).…”