Neuroinflammation as Fuel for Axonal Regeneration in the Injured Vertebrate Central Nervous System

Abstract

Damage to the central nervous system (CNS) is one of the leading causes of morbidity and mortality in elderly, as repair after lesions or neurodegenerative disease usually fails because of the limited capacity of CNS regeneration. The causes underlying this limited regenerative potential are multifactorial, but one critical aspect is neuroinflammation. Although classically considered as harmful, it is now becoming increasingly clear that inflammation can also promote regeneration, if the appropriate context is provided. Here, we review the current knowledge on how acute inflammation is intertwined with axonal regeneration, an important component of CNS repair. After optic nerve or spinal cord injury, inflammatory stimulation and/or modification greatly improve the regenerative outcome in rodents. Moreover, the hypothesis of a beneficial role of inflammation is further supported by evidence from adult zebrafish, which possess the remarkable capability to repair CNS lesions and even restore functionality. Lastly, we shed light on the impact of aging processes on the regenerative capacity in the CNS of mammals and zebrafish. As aging not only affects the CNS, but also the immune system, the regeneration potential is expected to further decline in aged individuals, an element that should definitely be considered in the search for novel therapeutic strategies.

Figure 1

Summary of the current knowledge of the role of acute inflammation in axonal regeneration, in mammals and zebrafish. (a) After optic nerve injury in mammals, surveying retinal microglia become reactivated, proliferate, and transform into amoeboid microglia. Inflammatory stimulation (green arrows), which can be achieved via administration of TLR2 agonists or lens injury, further induces micro- and macroglial cell activation and an influx of neutrophils and blood-borne macrophages to the vitreous. Infiltrating macrophages and neutrophils secrete oncomodulin (Ocm), an inflammatory mediator that is thought to act on RGCs directly. Moreover, inflammatory stimulation elicits the secretion of IL-6 family cytokines from reactive astrocytes. Signal transduction of these cytokines is primarily mediated via the JAK/STAT3 and mTOR pathways in RGCs. Thus, inflammatory stimulation activates the intrinsic growth state of RGCs, and when combined with SOCS3 and/or PTEN deletion, feedback inhibitors of the JAK/STAT3 and mTOR pathway, respectively, axon regeneration beyond the glial scar can be obtained. (b) After an injury in the mammalian spinal cord microglia are activated, and neutrophils and blood-borne macrophages are recruited to the lesion site. Microglia/macrophages mostly adopt the proinflammatory phenotype and secrete proinflammatory cytokines such as TNF-α and IL-1β, while anti-inflammatory microglia/macrophages, which produce anti-inflammatory cytokines including IL-4 and IL-10, only represent a small percentage. Since the proinflammatory type is associated with adverse effects on regeneration, while anti-inflammatory cells are assumed to be protective and growth-promoting, treatments that stimulate anti-inflammatory activation at the expense of the proinflammatory type (green arrows) improve axonal growth beyond the glial scar and coincide with a better regenerative outcome. (c) Stimulation of acute inflammation after optic nerve injury in zebrafish activates microglia and induces recruitment of neutrophils and blood-borne macrophages, mirroring the situation in mammals. This results in an acceleration of the spontaneous regenerative process. Although it has already been shown that LIF and the JAK/STAT3 and mTOR pathways are implicated in optic nerve regeneration in zebrafish as well, the precise mechanism of how the positive effects of acute inflammation is mediated remains elusive. (d) After a spinal cord injury in zebrafish, microglia are activated and neutrophils and blood-borne macrophages infiltrate the lesion site, although their precise contribution to axonal regeneration is still unknown. Despite pro- and anti-inflammatory macrophages have been described in zebrafish injury models outside the CNS, the polarization of microglia/macrophages after spinal cord injury has not yet been studied. Strikingly, a growth-permissive glial bridge is formed at the lesion site, while glial scar is absent in zebrafish.

Figure 2

Intravitreal injection of zymosan accelerates axonal regeneration in zebrafish. (a) Representative images of biocytin-labeled axons in the contralateral optic tectum of naive fish (left) and fish treated with vehicle or zymosan, at 7 days after optic nerve injury (middle and right, resp.). The stratum opticum (SO), the layer through which the RGC axons innervate the tectum, is indicated. Scale bar = 50 µm. (b) Quantification of the reinnervated area of the optic tectum in fish treated with vehicle or zymosan at 7 days after injury, relative to naive fish. Intravitreal injection of zymosan significantly accelerates reinnervation, which is already close to naive levels in zymosan treated fish as compared to vehicle-injected fish. Data represent mean ± SEM (n ≥ 3 animals per group, ^∗p < 0.05, and ^∗∗p < 0.01).