Monocyte invasion into the retina restricts the regeneration of neurons from Müller glia.

Abstract

Endogenous reprogramming of glia into neurogenic progenitors holds great promise for neuron restoration therapies. Using lessons from regenerative species, we have developed strategies to stimulate mammalian Müller glia to regenerate neurons in vivo in the adult retina. We have demonstrated that the transcription factor Ascl1 can stimulate Müller glia neurogenesis. However, Ascl1 is only able to reprogram a subset of Müller glia into neurons. We have reported that neuroinflammation from microglia inhibits neurogenesis from Müller glia. Here we find that the peripheral immune response is a barrier to CNS regeneration. We show that monocytes from the peripheral immune system infiltrate the injured retina and negatively influence neurogenesis from Müller glia. Using CCR2-knockout mice of both sexes we find that preventing monocyte infiltration improves the neurogenic and proliferative capacity of Müller glia stimulated by Ascl1. Using scRNA-seq analysis we identified a signaling axis wherein Osteopontin, a cytokine highly expressed by infiltrating immune cells is sufficient to suppress mammalian neurogenesis. This work implicates the response of the peripheral immune system as a barrier to regenerative strategies of the retina.Significance Statement Regeneration of neurons in the central nervous system is extremely limited in mammals. Transgenic overexpression of the proneural transcription factor Ascl1 enables mammalian retinal glia to regenerate some neurons lost to injury. We found that during this regenerative response to injury, monocytes from the periphery invade the neural retina and these inflammatory cells negatively regulate the ability of Müller glia to reprogram into neurogenic progenitors. When monocytes are inhibited from infiltrating the retina, regeneration of neurons from Müller glia is significantly enhanced. This work implicates peripheral immunomodulation as a tool to enhance endogenous neuronal replacement strategies.