Retinal microglia: Just bystander or target for therapy?

Karlstetter, Marcus; Scholz, Rebecca; Rutar, Matt; Wong, Wai T.; Provis, Jan; Langmann, Thomas

doi:10.1016/j.preteyeres.2014.11.004

Cited by 455 publications

(431 citation statements)

References 335 publications

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“…Collectively, these results and other recent findings support the notion that manipulation of neuroimmune interactions could be a useful means of stimulating reparative processes in patients with degenerative the CNS disorders (43). One promising immunomodulatory candidate is the mesencephalic astrocyte-derived neurotrophic factor (MANF).…”

Section: Immunomodulator-induced Resolution Of Activated Microgliasupporting

confidence: 67%

“…2 I and I′), and the number of microglia cell bodies per each retinal layer was quantified. Embryonic and larval zebrafish microglia cell bodies have been shown to reside in the nerve fiber layer (NFL, or vitreal surface), ganglion cell layer, and inner nuclear layer (INL) but to be largely excluded from the photoreceptor and plexiform layers (42), in contrast to observations in mammalian systems (43). Data from uninjured controls are in agreement with these findings; the majority of microglia localized to the NFL and showed no evidence of active translocation between different retinal layers in the absence of injury (Fig.…”

Section: Additional Hallmarks Of Microglia Activation Following Rod Cmentioning

confidence: 89%

“…Co-Abl, coablated retinas; Rod-Abl, rod photoreceptor ablated retinas. chronic inflammation and related immune cell infiltration of the CNS are believed to exacerbate neurodegenerative pathologies (43). Interestingly, zebrafish regenerate neural tissue despite mounting an inflammatory response to injury (58).…”

Section: Discussionmentioning

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.

160

218

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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: Immunomodulator-induced Resolution Of Activated Microgliasupporting

confidence: 67%

Section: Additional Hallmarks Of Microglia Activation Following Rod Cmentioning

confidence: 89%

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.

160

218

View full text Add to dashboard Cite

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“…Behavior and Activation-Retinal microglial cells, the resident ocular macrophages, are immunocompetent cells that respond to inflammation and infection, phagocytosing debris produced during normal physiological remodeling or degenerative diseases (36). Microglia-deficient mice were found to have reduced numbers of vascular branch points with fewer points of contact between neighboring tip cells in the retina, suggesting that microglia provide scaffolds for sprout fusion and anastomosis (37).…”

Section: Mir-155/ccn1 Regulatory Axis Modulates Microglial Cellmentioning

confidence: 99%

Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia

Yan

Lee

Lazzaro

et al. 2015

Journal of Biological Chemistry

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Background: MicroRNA-155 is a proinflammatory small RNA, but its function in pathological angiogenesis is unknown. Results: MicroRNA-155 deficiency increases angiogenic protein CCN1 expression, which harnesses retinal neovascularization by reducing both microglia activation and inflammation. Conclusion: The microRNA-155/CCN1 regulatory axis regulates angiogenic and inflammatory responses in the retina. Significance: Modulation of microRNA-155 and CCN1 interaction is potentially beneficial in retinal neovascularization therapy.

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“…Microglia, the main retinal immune cells (macrophages) especially play a key role both in degenerative and inflammatory retinal diseases (Fritsche et al, 2014; Karlstetter, Scholz, Rutar, Wong, & Provis, 2015). Additionally, other cell types present at the vitreoretinal interface, such as hyalocytes, may contribute to the ERM contraction (Kohno et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

et al. 2018

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Aging is a phenomenon that is associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision‐threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. iERM is characterized by fibrous tissue developing on the surface of the macula, which leads to biomechanical and biochemical macular damage. MH is a small breakage in the macula and is associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry‐based label‐free quantitative proteomics analysis of the vitreous proteomes from patients with iERM and MH to identify the key proteins, as well as the multiple interconnected biochemical pathways, contributing to the development of these diseases. We identified a total of 1,014 unique proteins, many of which are linked to inflammation and the complement cascade, revealing the inflammation processes in retinal diseases. Additionally, we detected a profound difference in the proteomes of iEMR and MH compared to those of diabetic retinopathy with macular edema and rhegmatogenous retinal detachment. A large number of neuronal proteins were present at higher levels in the iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins, and signaling molecules, pointing toward the important role of neurodegenerative component in the pathogenesis of age‐related vitreoretinal diseases. Despite them having marked similarities, several unique vitreous proteins were identified in both iERM and MH, from which candidate targets for new diagnostic and therapeutic approaches can be provided.

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Retinal microglia: Just bystander or target for therapy?

Cited by 455 publications

References 335 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

Single and Compound Knock-outs of MicroRNA (miRNA)-155 and Its Angiogenic Gene Target CCN1 in Mice Alter Vascular and Neovascular Growth in the Retina via Resident Microglia

Systems pathology analysis identifies neurodegenerative nature of age‐related vitreoretinal interface diseases

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