Neuroinflammation and Optic Nerve Regeneration: Where Do We Stand in Elucidating Underlying Cellular and Molecular Players?

Abstract

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.

Müller glia–myeloid cell crosstalk accelerates optic nerve regeneration in the adult zebrafish

“…As such, the spontaneously regenerating adult zebrafish provides the ideal model organism to further disentangle which different cells and molecules contribute to the proregenerative outcome of inflammatory stimulation. A first query to be tackled is the identification and role of the different immune cell types at play during the regenerative process, which still remains a matter of debate (Andries et al, 2020). In this view, Tsarouchas et al (2018), who used different transgenic and mutant zebrafish lines, reported that neutrophil‐derived il‐1β first promotes but thereafter counteracts axonal regrowth after spinal cord injury.…”

“…In contrast, Irf8 mutant zebrafish larvae, with strongly reduced numbers of microglia/macrophages, were found to display a defective functional recovery, while axonal regeneration remained unaffected in microglia‐deficient csf1ra/b larvae (Tsarouchas et al, 2018). These results suggest that a biphasic inflammatory response, with an early proinflammatory phase (dominated by neutrophils) followed by a late anti‐inflammatory phase (with macrophages as the primary actors), might be necessary at the site of injury for successful regeneration (Andries et al, 2020; Tsarouchas et al, 2018). Also in our study, neutrophils were the first cells to be detected in the inflamed retina and were present throughout the early inflammatory response.…”

“…Alternatively, it is highly likely that rather a timed crosstalk between certain cell types or their factors influences the regenerative outcome, as this has been shown to significantly shape the overall injury response in different disease models (Gao et al, 2013; Karve, Taylor, & Crack, 2016; Liddelow et al, 2017). Nevertheless, the precise mechanisms as well as the relative contributions of the different inflammatory and glial cell types are not yet fully elucidated, and studies addressing this in the context of optic nerve regeneration remain scarce (Andries, De Groef, & Moons, 2020). More research is thus highly recommended to unravel the molecular cues and downstream signaling pathways that mediate the effects of inflammatory stimulation on axonal regeneration.…”

The basic science of optic nerve regeneration

“…In the first week following ONC the inflammatory response reaches its peak. Infiltrating monocyte-derived macrophages arrive at the optic nerve after the first day (5,48). Of note, immunohistochemical classification of microglia vs. macrophages (and thus, their relative contributions) remains difficult, as macrophages take on a microglia-like molecular profile upon infiltration and activation in the CNS (49,50); however, recent retinal single-cell profiling experiments have made huge strides in determining the full complement of different myeloid cells involved in injury responses (51).…”

“…However, knowledge about axonal destruction and regeneration is fast accumulating, bringing us closer to developing regenerative therapies for CNS tissues. Many other excellent reviews have covered the topic of RGC regeneration (1)(2)(3)(4)(5), each from its own perspective. Some discuss the generation and transplantation of new RGCs; others investigate potential pro-regenerative paracrine effects of mesenchymal stem cell replacement therapies (6,7).…”