Abstract
Purpose :
Recovery after retinal and optic injury is directly tied to aging. As we age there are intrinsic signals within retinal ganglion cells (RGCs) and extrinsic responses including the inflammatory response that significantly contribute to inhibition of repair. How the aging immune system responds to optic nerve injury is not well understood. Animal model studies have demonstrated that younger mice can have immune cell mediated RGC repair after injury, however, to date, no one has evaluated aged mice for their ability to regenerate axons after transection.
Methods :
We used the ONC model of acute axonal transection in young (3 months) and aged mice (18 months). Mice were subjected to ONC and either intraocular (i.o.) zymosan (zym) or i.o. adoptive transfer of young or aged zym stimulated neutrophils. End point analysis examined i.o. and blood myeloid cells by flow cytometry, or axon regeneration by cholera toxin B i.o. injection.
Results :
We identified that immune mediated regeneration of axons after transection in young mice is driven by an alternatively activated neutrophil, characterized as Ly6Glow CD101- CD14+ and arginase1+ (Arg+). In aged mice (18 months), neutrophils recruited after ONC+i.o zym are classically activated with high expression of Ly6G and CD101 compared to the neutrophils found in young mice. These aged mature neutrophils produce high levels of IL-1b and TNFa compared to younger neutrophils, and aged mice had decreased axon regeneration and decreased RGC survival compared to younger mice. Adoptive transfer of young neutrophils into aged mice and aged neutrophils into young mice subjected to ONC found aged mice that received young neutrophils to have more regeneration, compared to aged mice that that received aged neutrophils or the young mice that received aged neutrophils indicating that neutrophil age contributes to axon regeneration.
Conclusions :
These studies have shown that neutrophils in aged mice (18 months) do not assume an alternative polarization state seen in young mice (3 months) and aged mice have poorer regeneration. Reciprocal adoptive transfer studies suggest that the age the immune cell, not just neuron age, also impacts the ability of injured neurons to regenerate after transection. Future work to understand the key intrinsic and extrinsic factors that determine aging neutrophil responses.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.