Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Zhang, Zhiqiang; Hou, Hongying; Yu, Song; Zhou, Chixing; Zhang, Xiaoli; Li, Na; Zhang, Shuqiang; Song, Kaida; Lu, Ying; Liu, Dong; Lü, Hong; Xu, Hui

doi:10.1002/glia.23707

Cited by 57 publications

(78 citation statements)

References 47 publications

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“…The role of the immune system in neurodegenerative disease is complex, with evidence of both beneficial and deleterious roles (11,(24)(25)(26). Data from our lab and others support contextdependent roles for microglia during neural regeneration, with evidence of both pro-and antiregenerative effects (9,10,27,28). Collectively, these data support the concept that modulating macrophage/microglia reactivity may provide a therapeutic strategy for promoting neural repair in humans (29,30).…”

Section: Discussionsupporting

confidence: 69%

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

Emmerich

White

Kambhamptati

et al. 2020

Preprint

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Retinal regeneration occurs naturally in zebrafish but not in mammals. A thorough understanding of the mechanisms regulating regeneration may help to advance strategies for stimulating retinal repair in humans. We previously implicated microglia as key regulators of retinal regeneration using a zebrafish model of inducible photoreceptor degeneration. Intriguingly, post-injury treatments with the immune suppressant dexamethasone (Dex) resulted in accelerated photoreceptor regeneration. Modifying microglia responses to retinal cell death may therefore promote neuroregenerative processes. Here, we investigated the effect of Dex on microglia reactivity in the regenerating zebrafish retina using adaptive optics-corrected lattice light-sheet microscopy. Quantitative analysis of in vivo time-lapse imaging data revealed that Dex inhibited microglia migration speed, consistent with an immunosuppressive effect. Unfortunately, long-term treatment with glucocorticoids, including Dex, causes adverse side effects which limits their use therapeutically. To overcome this limitation, a nanoparticle-based drug delivery strategy was used to target Dex to reactive microglia. We show that conjugating Dex to dendrimer nanoparticles: 1) dramatically decreased toxicity in larval zebrafish, 2) succeeded in selective targeting of reactive microglia and, 3) resulted in “super-accelerated” photoreceptor regeneration kinetics. These data support the use of dendrimer-based drug formulations for modulating microglia reactivity in degenerative disease contexts, especially as therapeutic strategies for promoting regenerative responses to neuronal cell loss.

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Section: Discussionsupporting

confidence: 69%

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

Emmerich

White

Kambhamptati

et al. 2020

Preprint

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“…Some of this information has led to studies showing that mammalian Müller glia possess latent regenerative potential that can be augmented by reprogramming these cells, and that MG-derived progenitors can regenerate some neurons (including photoreceptors) [7,25,8,[42][43][44], but this neuronal regeneration is very inefficient [9,41]. In the injured zebrafish retina, inflammation is necessary and sufficient for neuronal regeneration to begin [45,17,18,46,20,19,23,21,22], but in the injured mammalian retina, inflammation prevents Müller glia from initiating a regenerative response [25]. When inflammation is mis-regulated in the injured zebrafish retina, this leads to aberrant proliferation of MGderived progenitors and alters photoreceptor regeneration [21,20], showing the importance of precise inflammatory regulation in controlling these events.…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation occurs in response to tissue injury, and several recent studies show that activation of neuroinflammatory pathways is both necessary and sufficient to initiate neuronal (including photoreceptor) regeneration in the zebrafish retina [17][18][19][20][21][22] [reviewed in 23,24]. Inflammatory signals seem to have the opposite effect in the injured mammalian retina, in which removal of microglia reduces inflammatory gene expression and increases the number of regenerated neurons [25].…”

mentioning

confidence: 99%

Disruption ofmiR-18aalters proliferation, photoreceptor replacement kinetics, inflammatory signaling and microglia/macrophage numbers during retinal regeneration in zebrafish

Magner

Sandoval-Sanchez

Hitchcock

et al. 2021

Preprint

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In mammals, photoreceptor loss causes permanent blindness, but in zebrafish (Danio rerio), Müller glia function as intrinsic stem cells, producing progenitor cells that regenerate photoreceptors and restore vision. MicroRNAs (miRNAs) critically regulate neurogenesis in the brain and retina, but the roles of miRNAs in injury-induced neuronal regeneration are largely unknown. The miRNA miR-18a regulates photoreceptor differentiation in the embryonic retina. The purpose of the current study was to determine the function of miR-18a during injury-induced photoreceptor regeneration. RT-qPCR, in-situ hybridization (ISH) and immunohistochemistry (IHC) showed that miR-18a expression increases throughout the retina by 1-day post-injury (dpi) and continues to increase through 5 dpi. Bromodeoxyuridine (BrdU) labeling showed that at 7 and 10 dpi, when regenerated photoreceptors are normally differentiating, there are more proliferating Müller glia-derived progenitors in homozygous miR-18a mutant (miR-18ami5012) retinas compared with wild type (WT), indicating that miR-18a negatively regulates injury-induced proliferation. At 7 and 10 dpi, miR-18ami5012 retinas have fewer mature photoreceptors than WT, but there is no difference at 14 dpi, revealing that photoreceptor regeneration is delayed. BrdU labeling showed that the excess progenitors in miR-18ami5012 retinas migrate to other retinal layers besides the photoreceptor layer. Inflammation is critical for photoreceptor regeneration and RT-qPCR showed that, in the absence of miR-18a, inflammation is prolonged. Suppressing inflammation with dexamethasone rescues the miR-18ami5012 phenotype. Together, these data show that during injury-induced photoreceptor regeneration, miR-18a regulates proliferation and photoreceptor regeneration by regulating key aspects of the inflammatory response during photoreceptor regeneration in zebrafish.

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“…These results are consistent with findings in other systems, where the mTOR pathway has been shown to exert a pro-regenerative role. Indeed, in the zebrafish retina, mTOR is activated in Müller glia within 6 hours after injury and expression is maintained in proliferating Müller glia and Müller glia-derived progenitor cells (MGPCs) (32). In this system, mTOR activity is required both for the dedifferentiation of Müller glia to generate progenitors as well as the proliferation of the progenitor cells themselves.…”

Section: Discussionmentioning

confidence: 99%

mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish

Leach

Gross

2021

Preprint

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The retinal pigment epithelium (RPE) plays numerous critical roles in maintaining vision and this is underscored by the prevalence of degenerative blinding diseases like age-related macular degeneration (AMD), in which visual impairment is caused by progressive loss of RPE cells. In contrast to mammals, zebrafish possess the ability to intrinsically regenerate a functional RPE layer after severe injury. The molecular underpinnings of this regenerative process remain largely unknown yet hold tremendous potential for developing treatment strategies to stimulate endogenous regeneration in the human eye. In this study, we demonstrate that the mTOR pathway is activated in RPE cells post-genetic ablation. Pharmacological and genetic inhibition of mTOR activity impaired RPE regeneration, while mTOR activation enhanced RPE recovery post-injury, demonstrating that mTOR activity is necessary and sufficient for RPE regeneration in zebrafish. RNA-seq of RPE isolated from mTOR-inhibited larvae identified a number of genes and pathways dependent on mTOR activity at early and late stages of regeneration; amongst these were components of the immune system, which is emerging as a key regulator of regenerative responses across various tissue and model systems. Our results identify crosstalk between macrophages/microglia and the RPE, wherein mTOR activity in the RPE is required for recruitment of macrophages/microglia to the injury site. In turn, these macrophages/microglia reinforce mTOR activity in regenerating RPE cells. Interestingly, the function of macrophages/microglia in maintaining mTOR activity in the RPE appeared to be inflammation-independent. Taken together, these data identify mTOR activity as a key regulator of RPE regeneration and link the mTOR pathway to immune responses in facilitating RPE regeneration.

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Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Cited by 57 publications

References 47 publications

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

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

Disruption ofmiR-18aalters proliferation, photoreceptor replacement kinetics, inflammatory signaling and microglia/macrophage numbers during retinal regeneration in zebrafish

mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish

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