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Purpose Neurons in the mammalian central nervous system (CNS) fail to regenerate their axons after injury and undergo axonal degeneration, dendritic shrinkage and eventually apoptosis. However, after inflammatory stimulation (IS), retinal ganglion cells (RGCs) are transformed into an active regenerative state. Several players essential to this regeneration-promoting effect of controlled inflammation have been identified. However, our understanding of the multiple glial- or macrophage-derived factors that may synergistically contribute or potentiate the beneficial effects of IS, is still incomplete. Multiple research lines suggest that matrix metalloproteinases (MMPs) are important players in CNS development, where they contribute to axonal navigation, dendritic tree refinement, etc… However, their in vivo functions during de- and regeneration in the adult mammalian brain remain largely elusive. Here, we investigated the effect of MMP-2 downregulation on dendrite remodeling and axonal regeneration after optic nerve crush (ONC) injury (degeneration model) and ONC combined with IS (regeneration model) in the mouse visual system. Methods IS, induced via intravitreal injections of zymosan or Pam3Cys, was used to induce axonal regeneration after ONC in both wild-type and Mmp-2-/- mice. Dendritic remodeling was examined via optical coherence tomography (OCT), (immune)histological stainings on retinal sections and western blots for microtubule associated protein (MAP)-2. In addition, axonal regeneration was assessed by quantifying fluorescently labelled cholera toxin beta (CTB-alexa 488)-positive axons in optic nerve sections. Results Our results revealed that, of all paradigms tested, Pam3Cys combined with cAMP form the best method to induce axonal regeneration. OCT- and histological analyses showed thinning of the inner plexiform layer (IPL), containing the RGC dendrites, upon injury. Strikingly, MAP-2c, typically expressed in the developing CNS, becomes upregulated in the IPL, while MAP 2a+b, normally present in the adult CNS, is downregulated. After injury, MMP-2 expression was highly increased in the inner retina, where it is localized in Muller glia, and in infiltrating immune cells in the vitreous. Interestingly, IPL shrinkage could not be observed in the retina of Mmp-2-/- mice. In addition, also a lower number of CTB+ regenerating axons was found in the optic nerves of Mmp-2-/- mice, as compared to wild-type animals. Conclusion Taken together, our results suggest that MMP-2 plays a beneficial role during axonal regeneration and affects both dendritic and axonal processes in the injured mouse retina/optic nerve. Furthermore, its expression by invading immune cells puts MMP-2 forward as a molecule linking inflammatory stimulation to enhanced axonal regeneration. Additional research is needed to unravel the presumed pleiotropic function of MMP-2 during these regenerative processes.