Inflammation and matrix metalloproteinase 9 (Mmp‐9) regulate photoreceptor regeneration in adult zebrafish

Abstract

Brain injury activates complex inflammatory signals in dying neurons, surviving neurons, and glia. Here, we establish that inflammation regulates the regeneration of photoreceptors in the zebrafish retina and determine the cellular expression and function of the inflammatory protease, matrix metalloproteinase 9 (Mmp-9), during this regenerative neurogenesis. Following photoreceptor ablation, anti-inflammatory treatment suppresses the number of injury-induced progenitors and regenerated photoreceptors. Upon photoreceptor injury, mmp-9 is induced in Müller glia and Müller glia-derived photoreceptor progenitors. Deleting mmp-9 results in over production of injury-induced progenitors and regenerated photoreceptors, but over time the absence of Mmp-9 compromises the survival of the regenerated cones. At all time-points studied, the levels of tnf-α are significantly elevated in mutant retinas.Anti-inflammatory treatment in mutants rescues the defects in cone survival. These data provide a link between injury-induced inflammation in the vertebrate CNS, Mmp-9 function during neuronal regeneration and the requirement of Mmp-9 for the survival of regenerated cones.

Inflammation Regulates the Multi-Step Process of Retinal Regeneration in Zebrafish

“…Following this, the progeny of Müller glia proliferate rapidly, migrate to the various cellular layers of the retina that have been damaged, and there reveal their multipotential nature by differentiating into any type of retinal neuron [ 43 ]. In the teleost retina, the parallels between the growth-associated rod genesis and neuronal regeneration are obvious, but, as we review below, neuronal regeneration originating from Müller glial lineages is driven by the inflammatory response [ 6 , 44 ]. Perhaps inferred a priori , it was recently established that the cell fate-determination programs that regulate retinal development are recapitulated during the final stages of regeneration and serve to govern differentiation, process of outgrowth and the re-establishment of synaptic circuits among the regenerated neurons [ 45 ].…”

Role of Macrophages and Microglia in Zebrafish Regeneration

“…The phagocytic behavior of immune cells is potentially important in the establishment of new connections in the brain, as degenerating connections first must be removed before new connections can form [ 147 ]. For example, injury in the zebrafish is followed quickly by a microglial inflammatory response, characterized by morphological modification and leukocyte accumulation at the injury site [ 112 , 120 , 122 , 148 ]. There is also an increase in proliferation of ependymal glial cells that produces intermediate neural progenitors [ 85 , 149 ] that aid in replacing damaged neurons.…”

“…Many microglial studies in fish examine photoreceptor regeneration [ 112 , 158 , 173 ]. These types of studies on cellular and molecular mechanisms and inflammation have the potential to elucidate the regenerative potential of mammalian tissues [ 174 , 175 ].…”

Dendrimer-targeted immunosuppression of microglia reactivity super-accelerates photoreceptor regeneration kinetics in the zebrafish retina

“…Broadly, nanoparticle-based modulation of immune system responses to neuronal cell death may represent a generalizable strategy for enhancing neural stem cell activity. However, accelerated regenerative processes in zebrafish do not necessarily equate to improved functional recovery (43,44) nor to enhanced regenerative capacities in mammals. Additional studies will be required to test how accelerated retinal cell regeneration correlates to the recovery of visual deficits and to assess targeted immunomodulation in mammalian retinal degeneration models.…”