Neuroinflammation as driving force for axonal regeneration in the adult mouse visual system: MMP2 as a possible modulator

Neurodegenerative disorders such as Alzheimer's (AD), Parkinson's (PD), and Huntington's disease, multiple sclerosis (MS), glaucoma, etc., represent a growing social and economic problem. This irreversible diseases usually occur later in life and affect an increasing number of people in our the aging society. Neurotrauma or degeneration drastically diminishes the quality of life and leads to severe impairments, largely because the central nervous system (CNS) in adult mammals has only a limited capacity to replace lost neurons (de novo neurogenesis), or - the focus of this study - to repair damaged axons (axonal regeneration) [1-4]. Indeed, once mammals surpass the postnatal phase, they loose their regenerative potential in the CNS due to the low intrinsic growth capacity of their neurons, the presence of extrinsic inhibitors and the loss of neurotrophic support [5-9]. Restoration of neuronal function after damage to the CNS involves effectuating neuroprotection, inducing axonal regeneration and/or de novo neurogenesis, stimulating correct axonal navigation, and reinnervation of the targets in the brain [10]. Despite decades of research efforts, full recovery after CNS injury or disease continues to be a challenge [4]. Thorough investigation of the mechanisms that contribute to successful axonal regeneration therefore remains essential, and can provide new insights in the development of strategies for functional recovery of neuronal projections in the CNS of adult mammals [5-7,9,11,12]. Since several years, neuroinflammation has been suggested as a mechanism that can stimulate the regeneration capacity of the CNS [13-15]. Where the inflammatory response was seen as a harmful process in the past, it is increasingly clear that inflammatory cells actually contribute to CNS repair by their positive impact on - among other things - axonal regeneration [13,16-18]. Yet, little is known about how inflammation may contribute to successful axonal regeneration in the CNS. Therefore, the overall aim of this project is to unravel the cellular and molecular mechanisms by which inflammation modulates axonal regeneration. In this researchproject, we will investigate axonal regeneration in the optic nerve. Indeed, the retinofugale system is a powerful model for studying axonal regeneration and identifying the underlying molecules and signaling pathways. It has already contributed significantly to the current understanding of the multifactorial causes that underlie the failure of axonal regeneration in the CNS of adult mammals. More specifically, we will use a validated inflammatory regenerative optic nerve crush (RONC) model in the mouse, which induces axonal regeneration, via controlled ocular inflammation. Based on an innovative comparative quantitative proteomics, we will identify novel molecules and map the signaling pathways, which link controlled inflammation to axonal regeneration. On the other hand, we will also build on earlier findings from the host lab, which suggest that matrix metalloproteinase-2 (MMP-2) is a key player during the initiation of axonuitgroei, possibly through effects on inflammation, as well as during axonelongation. In summary, the investigation of axonal regeneration is a challenge, but is essential for promoting CNS recovery and the fight for healthy aging. In this study we focus on the role of the innate immune system during axonal regeneration, and we are systematically searching for factors that link the natural process of inflammation to successful regeneration.status: publishe

Neuroinflammation and optic nerve regeneration: where do we stand in elucidating underlying cellular and molecular players?

Neurodegenerative diseases and central nervous system (CNS) trauma are highly irreversible, in part because adult mammals lack a robust regenerative capacity. A multifactorial problem underlies the limited axonal regeneration potential. Strikingly, neuroinflammation seems able to induce axonal regrowth in the adult mammalian CNS. It is increasingly clear that both blood-borne and resident inflammatory cells as well as reactivated glial cells affect axonal regeneration. The scope of this review is to give a comprehensive overview of the knowledge that links inflammation (with a focus on the innate immune system) to axonal regeneration and to critically reflect on the controversy that still prevails about the cells, molecules and pathways that are dominating the scene. Also, a brief overview is given of what is already known about the crosstalk between and the heterogeneity of cell types that might play a role in axonal regeneration. Recent research indicates that inflammation-induced axonal regrowth is not solely driven by a single-cell population but probably relies on the crosstalk between multiple cell types and the strong regulation of these cell populations in time and space. Moreover, there is growing evidence that the different cell populations are highly heterogeneous and as such can react differently upon injury. This could explain the controversial results that have been obtained over the past years. The primary focus of this manuscript is the retinofugal system of adult mammals, however, when relevant, insights or examples of the spontaneous regenerating zebrafish model and spinal cord research are added.status: publishe

Matrix metalloproteinases during axonal regeneration, a multifactorial role from start to finish

By proteolytic cleavage, matrix metalloproteinases (MMPs) not only remodel the extracellular matrix (ECM) but they also modify the structure and activity of other proteinases, growth factors, signaling molecules, cell surface receptors, etc. Their vast substrate repertoire adds a complex extra dimension of biological control and turns MMPs into important regulatory nodes in the protease web. In the central nervous system (CNS), the detrimental impact of elevated MMP activities has been well-described for traumatic injuries and many neurodegenerative diseases. Nonetheless, there is ample proof corroborating MMPs as fine regulators of CNS physiology, and well-balanced MMP activity is instrumental to development, plasticity, and repair. In this manuscript, we review the emerging evidence for MMPs as beneficial modulators of axonal regeneration in the mammalian CNS. By exploring the multifactorial causes underlying the inability of mature axons to regenerate, and describing how MMPs can help to overcome these hurdles, we emphasize the benign actions of these Janus-faced proteases.status: publishe

Neuroinflammation drives dendritic shrinkage and axonal regeneration in the injured mammalian central nervous system: MMP-2 as possible modulator

status: publishe

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

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

MMP-2 as a modulator of dendritic and axonal responses in the injured mammalian central nervous system

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, etcâ ¦ 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.status: publishe

MMP-2 as a modulator of dendritic shrinkage and axonal regeneration: neuroinflammation as the driving force

status: publishe

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

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.status: publishe