July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Complement is required for retinal ganglion cell axon regeneration following mouse optic nerve injury
Author Affiliations & Notes
  • Sheri Peterson
    Neurosurgery, Boston Childrens Hospital, Boston, Massachusetts, United States
    F. M. Kirby Neurobiology Center, Harvard Medical School, Boston, Massachusetts, United States
  • Yiqing Li
    Neurosurgery, Boston Childrens Hospital, Boston, Massachusetts, United States
    F. M. Kirby Neurobiology Center, Harvard Medical School, Boston, Massachusetts, United States
  • Kimberly A Wong
    Neurosurgery, Boston Childrens Hospital, Boston, Massachusetts, United States
    F. M. Kirby Neurobiology Center, Harvard Medical School, Boston, Massachusetts, United States
  • Larry Benowitz
    Neurosurgery, Boston Childrens Hospital, Boston, Massachusetts, United States
    F. M. Kirby Neurobiology Center, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Sheri Peterson, None; Yiqing Li, None; Kimberly Wong, None; Larry Benowitz, None
  • Footnotes
    Support  NEI T32 EY007145 (SLP); Adelson Medical Research Foundation (LIB); Neurosurgical Innovation and Research Endowed Chair (LIB)
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2802. doi:https://doi.org/
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    • Get Citation

      Sheri Peterson, Yiqing Li, Kimberly A Wong, Larry Benowitz; Complement is required for retinal ganglion cell axon regeneration following mouse optic nerve injury. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2802. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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  • Supplements
Abstract

Purpose : Axon regeneration failure in the mature central nervous system (CNS) underlies permanent functional deficit following clinical CNS trauma and disease. The complement cascade of the innate immune system normally responds to pathogen threat through inflammatory cell activation, pathogen opsonization, and pathogen lysis. However, several non-traditional roles for complement proteins in CNS development, injury, and disease have recently been described. We tested the hypothesis that the complement system affects retinal ganglion cell (RGC) survival and axon regeneration in an experimental model of CNS injury.

Methods : We assessed RGC axon regeneration and RGC survival in adult complement knockout (KO) mice (C3, C1q, CR3) in comparison to wildtype (WT) litterrmates (control group) 14 days after bilateral optic nerve crush with or without intraocular injections of known pro-regenerative and pro-survival treatments (zinc chelation, zymosan + cAMP, or AAV2-shPTEN + oncomodulin + cAMP). RGC regeneration was determined by the number of GAP43 immunolabeled axons 0.5mm past the optic nerve crush site. RGC survival was determined by the number of TUJ1 immunolabeled neurons in the ganglion cell layer of the retina. We characterized the cellular and protein inflammatory response to optic nerve injury as it relates to complement using retina and optic nerve tissue collected 1, 3, 5, 7 and 14 days post-injury and immunolabeled for complement proteins, complement receptors, microglia, astrocytes, and neurons.

Results : Inflammatory cells and complement proteins were present in the naive retina and optic nerve and increased following optic nerve injury. Axon growth induced by zinc chelation, inflammation, or combined pten deletion plus inflammation was reduced to 45%, 25% and 69% of WT, respectively, when C3 was deleted; to 22%, 40% and 63% of WT when C1q was deleted; and to 38%, 36% and 73% of WT when CR3 was deleted (N=3-23/group). Neither C3, C1q, nor CR3 KO consistently affected RGC survival with or without pro-survival treatments.

Conclusions : We report that treatment-induced RGC axon regeneration following optic nerve injury in mice requires complement proteins and a a complement receptor, consistent with our hypothesis. These data suggest that the complement system is required for axon regrowth in the mature mammalian CNS, and highlight a non-traditional role for the inflammatory complement system.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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