Acute Inflammation Initiates the Regenerative Response in the Adult Zebrafish Brain

Kyritsis, Nikos; Kızıl, Çağhan; Zocher, Sara; Kroehne, Volker; Kaslin, Jan; Freudenreich, Dorian; Iltzsche, Anne; Brand, Michael

doi:10.1126/science.1228773

Cited by 453 publications

(497 citation statements)

References 25 publications

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“…The innate immune system has been implicated in promoting epimorphic and tissue regeneration (8)(9)(10)(11); however its roles during cellular regeneration have only begun to be explored (15). We therefore investigated whether the innate immune system is responsive to selective ablation of rod photoreceptors using transgenic larvae in which rod cells and immune cells were labeled with the complementary fluorescent reporters rho:YFP-NTR and mpeg1.1:LOX2272-LOXP-tdTomato-LOX2272-Cerulean-LOXP-EYFP (39) (hereafter, mpeg1:Tomato) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate further roles of the innate immune system in retinal regeneration, we asked if chemical suppression of immune cell reactivity impacts the kinetics of rod cell replacement. Dexamethasone (Dex), a glucocorticoid receptor agonist, has been used to identify inflammatory signaling as a factor contributing to CNS regeneration in adult zebrafish following traumatic brain (11) and spinal cord (15) injuries. However, a role for inflammation in regulating regeneration following selective neuronal cell ablation has yet to be investigated.…”

Section: Microglia/macrophages Are Necessary For Normal Rod Photorecementioning

confidence: 99%

“…Recent studies have implicated innate immune cells in regulating tissue regeneration in the limb (8,9), heart (10), and brain (11). In addition, discrete immune cell types react to selective neuronal cell ablation in the peripheral (12) and central nervous systems in regenerative species (13)(14)(15).…”

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confidence: 99%

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Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

White¹,

Sengupta²,

Saxena³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

146

209

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Müller glia (MG) function as inducible retinal stem cells in zebrafish, completely repairing the eye after damage. The innate immune system has recently been shown to promote tissue regeneration in which classic wound-healing responses predominate. However, regulatory roles for leukocytes during cellular regeneration-i.e., selective cell-loss paradigms akin to degenerative disease-are less well defined. To investigate possible roles innate immune cells play during retinal cell regeneration, we used intravital microscopy to visualize neutrophil, macrophage, and retinal microglia responses to induced rod photoreceptor apoptosis. Neutrophils displayed no reactivity to rod cell loss. Peripheral macrophage cells responded to rod cell loss, as evidenced by morphological transitions and increased migration, but did not enter the retina. Retinal microglia displayed multiple hallmarks of immune cell activation: increased migration, translocation to the photoreceptor cell layer, proliferation, and phagocytosis of dying cells. To test function during rod cell regeneration, we coablated microglia and rod cells or applied immune suppression and quantified the kinetics of (i) rod cell clearance, (ii) MG/progenitor cell proliferation, and (iii) rod cell replacement. Coablation and immune suppressants applied before cell loss caused delays in MG/progenitor proliferation rates and slowed the rate of rod cell replacement. Conversely, immune suppressants applied after cell loss had been initiated led to accelerated photoreceptor regeneration kinetics, possibly by promoting rapid resolution of an acute immune response. Our findings suggest that microglia control MG responsiveness to photoreceptor loss and support the development of immune-targeted therapeutic strategies for reversing cell loss associated with degenerative retinal conditions. retina | microglia | glucocorticoid | regeneration | macrophage N eurodegenerative diseases are caused by the loss of discrete neuronal cell types. The goal of regenerative medicine is to reverse this process. One strategy for doing so involves harnessing the regenerative potential of endogenous neural stem cells. Unfortunately, although adult neural stem cells exist in the mammalian CNS, innate potentials for neuronal repair remain dormant in the absence of exogenous stimulation. Conversely, many other species are endowed with remarkable capacities for neuronal regeneration. For instance, in the zebrafish eye, retinal Müller glia (MG) cells can dedifferentiate to a stem cell-like state and give rise to progenitors that replace lost neurons and restore visual function (1, 2). Intriguingly, human MG cells are able to give rise to new neurons in culture (3) that can restore visual function when transplanted into mammalian disease models (4), suggesting that human MG retain a stem cell-like capacity for mediating retinal repair. Mechanisms controlling the regenerative potential of MG are therefore of great interest. We and others study zebrafish to learn more about how retinal regeneration is cont...

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Section: Resultsmentioning

confidence: 99%

Section: Microglia/macrophages Are Necessary For Normal Rod Photorecementioning

confidence: 99%

See 1 more Smart Citation

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

White¹,

Sengupta²,

Saxena³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

146

209

View full text Add to dashboard Cite

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“…Studies have shown that controlled amplification of initial inflammatory episodes has been associated with a shift in repair processes of different tissues towards more regeneration and less scar formation [22][23][24] . …”

Section: Discussionmentioning

confidence: 99%

Adipose tissue stromal vascular fraction in the treatment of full thickness burns in rats

Cardoso

Bachion²,

Morais³

et al. 2016

Acta Cir. Bras.

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PURPOSE:To analyze the healing effects of stromal vascular fraction (SVF) application compared to wound dressing with 2% silver sulfadiazine in full thickness burn wounds in rats. METHODS:Animals were divided into two groups: 2% silver sulfadiazine group and SVF group. Both groups received occlusive bandages while the first one was treated with 2% silver sulfadiazine and the latter was treated with injections of SVF prepared from adipose tissue extracted from an animal donor. The animals were accompanied through 3, 7 and 30 days for evaluation of macroscopic, microscopic and morphometric aspects. RESULTS:On day three, a significant increase (p<0.05) of infiltration of polymorphonuclear, fibrin formation and fibroblasts migration in SVF group was observed. On the 7 th day the mononuclear infiltrate, angiogenesis, collagen and fibroblasts were significantly increased in the SVF group (p<0.05). At 30 days significantly increased collagen deposition was observed in the SVF group (p<0.05). CONCLUSION:Adipose tissue derived stromal vascular fraction injections promotes better wound repair than 2% silver sulfadiazine in the treatment of full thickness burn in rats during the evaluated experimental period.

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“…Recent studies demonstrate that acute inflammation is required and sufficient to enhance proliferation of neural progenitors and subsequent neurogenesis after brain injury in zebrafish (23). In the embryonic stage, administration of IL-6 increases BrdU-labeled calretinin + neurons in the mouse olfactory bulb (24).…”

mentioning

confidence: 99%

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

Chen

Reed

Lane

2017

Proc. Natl. Acad. Sci. U.S.A.

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Adult neural stem cells/progenitor cells residing in the basal layer of the olfactory epithelium are capable of reconstituting the neuroepithelium even after severe damage. The molecular events underlying this regenerative capacity remain elusive. Here we show that the repair of neuroepithelium after lesioning is accompanied by an acute, but self-limited, inflammatory process. Attenuation of inflammatory cell recruitment and cytokine production by dexamethasone impairs proliferation of progenitor horizontal basal cells (HBCs) and subsequent neuronal differentiation. Using TNF-α receptor-deficient mice, we identify TNF-α signaling as an important contributor to this inflammatory and reparative process, mainly through TNF-α receptor 1. HBC-selective genetic ablation of RelA (p65), the transcriptional activator of the NF-κB pathway, retards inflammation and impedes proliferation at the early stages of regeneration and suggests HBCs directly participate in cross-talk between immune response and neurogenesis. Loss of RelA in the regenerating neuroepithelium perturbs the homeostasis between proliferation and apoptosis while enhancing JNK signaling. Together, our results support a model in which acute inflammation after injury initiates important regenerative signals in part through NF-κB-mediated signaling that activates neural stem cells to reconstitute the olfactory epithelium.neuroregeneration | inflammation | olfactory stem cells | NF-κB

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Acute Inflammation Initiates the Regenerative Response in the Adult Zebrafish Brain

Cited by 453 publications

References 25 publications

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

Adipose tissue stromal vascular fraction in the treatment of full thickness burns in rats

Acute inflammation regulates neuroregeneration through the NF-κB pathway in olfactory epithelium

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