Abstract
As adult mammals lack the capacity to replace or repair damaged neurons, degeneration and trauma (and subsequent dysfunction) of the central nervous system (CNS) seriously constrains the patient's life quality. Recent work has shown that appropriate modulation of acute neuroinflammation upon CNS injury can trigger a regenerative response; yet, the underlying cellular and molecular mechanisms remain largely elusive. In contrast to mammals, zebrafish retain high regenerative capacities into adulthood and thus form a powerful model to study the contribution of neuroinflammation to successful regeneration. Here, we used pharmacological immunosuppression methods to study the role of microglia/macrophages during optic nerve regeneration in adult zebrafish. We first demonstrated that systemic immunosuppression with dexamethasone (dex) impedes regeneration after optic nerve injury. Secondly, and strikingly, local intravitreal application of dex or clodronate liposomes prior to injury was found to sensitize retinal microglia. Consequently, we observed an exaggerated inflammatory response to subsequent optic nerve damage, along with enhanced tectal reinnervation. In conclusion, we found a strong positive correlation between the acute inflammatory response in the retina and the regenerative capacity of the optic nerve in adult zebrafish subjected to nerve injury.
Highlights
One of the first events manifesting upon central nervous system (CNS) injury is an acute immune response, which comprises the reactivation of resident microglia, and in severe cases the recruitment of leukocytes from the bloodstream
We studied the effect of systemic immunosuppression on optic nerve regeneration, using the anti-inflammatory drug dex
Our observation of microglial sensitization after local immunosuppression may be considered analogous to this concept of priming, as we demonstrate that immune cell sensitization affects the regenerative outcome after Optic Nerve Crush (ONC)
Summary
One of the first events manifesting upon central nervous system (CNS) injury is an acute immune response, which comprises the reactivation of resident microglia, and in severe cases the recruitment of leukocytes from the bloodstream. Leukocyte infiltration is characterized by rapid invasion of neutrophils and monocyte-derived macrophages, while lymphocytes may follow at later stages [1,2,3] All of these (re)activated immune cells secrete cytokines and chemokines, thereby modulating their environment and presumably affecting the neurodegenerative and the regenerative outcome [4, 5]. This acute inflammation has long been considered detrimental for functional recovery, there is compelling evidence that neuroinflammation may have beneficial effects – if properly orchestrated. In rodent models of optic nerve injury, the induction of a restricted ocular inflammation
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