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

Annelies Van Dyck, Ilse Bollaerts, An Beckers, Sophie Vanhunsel, Nynke Glorian, Jessie van houcke, Tjakko J. van Ham, Lies De Groef, Lien Andries, Lieve Moons*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)

Abstract

Neurodegenerative disorders, characterized by progressive neuronal loss, eventually lead to functional impairment in the adult mammalian central nervous system (CNS). Importantly, these deteriorations are irreversible, due to the very limited regenerative potential of these CNS neurons. Stimulating and redirecting neuroinflammation was recently put forward as an important approach to induce axonal regeneration, but it remains elusive how inflammatory processes and CNS repair are intertwined. To gain more insight into these interactions, we investigated how immunomodulation affects the regenerative outcome after optic nerve crush (ONC) in the spontaneously regenerating zebrafish. First, inducing intraocular inflammation using zymosan resulted in an acute inflammatory response, characterized by an increased infiltration and proliferation of innate blood-borne immune cells, reactivation of Müller glia, and altered retinal cytokine expression. Strikingly, inflammatory stimulation also accelerated axonal regrowth after optic nerve injury. Second, we demonstrated that acute depletion of both microglia and macrophages in the retina, using pharmacological treatments with both the CSF1R inhibitor PLX3397 and clodronate liposomes, compromised optic nerve regeneration. Moreover, we observed that csf1ra/b double mutant fish, lacking microglia in both retina and brain, displayed accelerated RGC axonal regrowth after ONC, which was accompanied with unusual Müller glia proliferative gliosis. Altogether, our results highlight the importance of altered glial cell interactions in the axonal regeneration process after ONC in adult zebrafish. Unraveling the relative contribution of the different cell types, as well as the signaling pathways involved, may pinpoint new targets to stimulate repair in the vertebrate CNS.

Original languageEnglish
Pages (from-to)1444-1463
Number of pages20
JournalGLIA
Volume69
Issue number6
Early online date27 Jan 2021
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
We thank Marijke Christiaens, Lut Noterdaeme and Véronique Brouwers for their technical support. We thank Plexxikon (Berkeley, CA, United States) for providing the PLX3397 compound, and Paul Martin (Bristol, United Kingdom) for the Lplastin primary antibody. This work was supported by the Research Council of KU Leuven (KU Leuven BOF‐OT/14/064) and the Research Foundation Flanders (FWO, G0B2315N and G053217N). Annelies Van Dyck, Ilse Bollaerts, An Beckers, Sophie Vanhunsel, Jessie Van Houcke and Lies De Groef were/are supported by a fellowship of the Research Foundation Flanders.

Publisher Copyright:
© 2021 Wiley Periodicals LLC.

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