Microglia: Key Players in Retinal Ageing and Neurodegeneration (original) (raw)
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Microglia Activation and Immunomodulatory Therapies for Retinal Degenerations
A chronic pro-inflammatory environment is a hallmark of retinal degenerative diseases and neurological disorders that affect vision. Inflammatory responses during retinal pathophysiology are orchestrated by microglial cells which constitute the resident immune cell population. Following activation, microglia cells lose their ramified protrusions, proliferate and rapidly migrate to the damaged areas and resolve tissue damage. However, sustained presence of tissue stress primes microglia to become overreactive and results in the excessive production of pro-inflammatory mediators that favor retinal degenerative changes. Consequently, interventions aimed at overriding microglial pro-inflammatory and pro-oxidative properties may attenuate photoreceptor demise and preserve retinal integrity. We highlight the positive effects of ligands for the translocator protein 18 kDa (TSPO) and the cytokine interferon beta (IFN-β) in modulating microgliosis during retinal pathologies and discuss their plausible mechanisms of action.
Experimental Eye Research, 2003
Many gaps exist in our knowledge of human retinal microglia in health and disease. We address the hypothesis that primary death of rod photoreceptors leads to activation of resident microglia in human retinas with retinitis pigmentosa (RP), late-onset retinal degeneration (L-ORD), or age-related macular degeneration (AMD). Regions of ongoing photoreceptor cell death were studied by immunocytochemistry with microglia-and other retinal cell-specific markers. In normal human retinas, quiescent microglia were small, stellate cells associated with inner retinal blood vessels. In retinas with RP, LORD , or AMD, numerous activated microglia were present in the outer nuclear layer in regions of ongoing rod cell death. These microglia were enlarged, amoeboid cells that contained rhodopsin-positive cytoplasmic inclusions. We conclude that activated microglia migrate to the outer nuclear layer and remove rod cell debris. In other central nervous system diseases such as stroke, activated microglia phagocytose debris from the primary injury and also secrete molecules that kill nearby normal neurons. By analogy with these diseases, we suggest that microglia activated by primary rod cell death may kill adjacent photoreceptors. Activated microglia may be a missing link in understanding why initial rod cell death in the human diseases RP, LORD , and AMD leads to death of the cones that are critical for high acuity daytime vision.
Microglia Inhibition Delays Retinal Degeneration Due to MerTK Phagocytosis Receptor Deficiency
Frontiers in Immunology, 2020
Retinitis Pigmentosa (RP) is a group of inherited retinal diseases characterized by progressive loss of rod followed by cone photoreceptors. An especially early onset form of RP with blindness in teenage years is caused by mutations in mertk, the gene encoding the clearance phagocytosis receptor Mer tyrosine kinase (MerTK). The cause for blindness in mutant MerTK-associated RP (mutMerTK-RP) is the failure of retinal pigment epithelial cells in diurnal phagocytosis of spent photoreceptor outer segment debris. However, the early onset and very fast progression of degeneration in mutMerTK-RP remains unexplained. Here, we explored the role of microglia in the Royal College of Surgeons (RCS) rat model of mutMerTK-RP. We found elevated levels of inflammatory cytokines and CD68 microglia activation marker, and more ionized calcium-binding adapter molecule 1 (Iba-1) positive microglia in RCS retina when compared to wild-type retina as early as postnatal day 14 (P14). Strikingly, renewal of photoreceptor outer segments in P14 wild-type rat retina is still immature with low levels of RPE phagocytosis implying that at this early age lack of this process in RCS rats is unlikely to distress photoreceptors. Although the total number of Iba-1 positive retinal microglia remains constant from P14 to P30, we observed increasing numbers of microglia in the outer retina from P20 implying migration to the outer retina before onset of photoreceptor cell death at ∼P25. Iba-1 and CD68 levels also increase in the retina during this time period suggesting microglia activation. To determine whether microglia affect the degenerative process, we suppressed retinal microglia in vivo using tamoxifen or a combination of tamoxifen and liposomal clodronate. Treatments partly prevented elevation of Iba-1 and CD68 and relocalization of microglia. Moreover, treatments led to partial but significant retention of photoreceptor viability and photoreceptor function. We conclude that loss of the phagocytosis receptor MerTK causes microglia activation and relocalization in the retina before lack of RPE phagocytosis causes overt retinal degeneration, and that microglia activities accelerate loss of photoreceptors in mutMerTK-RP. These results suggest that therapies targeting microglia may delay onset and slow the progression of this blinding disease.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016
Microglia, the principal resident immune cell of the CNS, exert significant influence on neurons during development and in pathological situations. However, if and how microglia contribute to normal neuronal function in the mature uninjured CNS is not well understood. We used the model of the adult mouse retina, a part of the CNS amenable to structural and functional analysis, to investigate the constitutive role of microglia by depleting microglia from the retina in a sustained manner using genetic methods. We discovered that microglia are not acutely required for the maintenance of adult retinal architecture, the survival of retinal neurons, or the laminar organization of their dendritic and axonal compartments. However, sustained microglial depletion results in the degeneration of photoreceptor synapses in the outer plexiform layer, leading to a progressive functional deterioration in retinal light responses. Our results demonstrate that microglia are constitutively required for ...
Cells
The retina is a highly metabolically active tissue with high-level consumption of nutrients and oxygen. This high metabolic demand requires a properly developed and maintained vascular system. The retina is nourished by two systems: the central retinal artery that supplies the inner retina and the choriocapillaris that supplies the outer retina and retinal pigment epithelium (RPE). Pathological neovascularization, characterized by endothelial cell proliferation and new vessel formation, is a common hallmark in several retinal degenerative diseases, including age-related macular degeneration (AMD). A limited number of studies have suggested that microglia, the resident immune cells of the retina, have an important role not only in the pathology but also in the formation and physiology of the retinal vascular system. Here, we review the current knowledge on microglial interaction with the retinal vascular system under physiological and pathological conditions. To do so, we first highl...
Disease models & mechanisms, 2015
Microglia serve key homeostatic roles, and respond to neuronal perturbation and decline with high spatiotemporal resolution. The course of all chronic CNS pathologies is thus paralleled by local microgliosis and microglia activation beginning at early stages. However, the possibility of using live monitoring of microglia during early disease progression to predict the severity of neurodegeneration has not been unexplored. Since the retina allows live tracking of fluorescent microglia in their intact niche, here we investigated their early changes in relation to later optic nerve neurodegeneration. Thus, we used the DBA/2J mouse model of inherited glaucoma, which develops progressive retinal ganglion cell degeneration of variable severity during aging, and thus represents a useful model to study pathogenic mechanisms of retinal ganglion cell decline similar to human glaucoma. We imaged CX3CR1(+/GFP) microglial cells in vivo at ages ranging from 1 to 5 months by confocal scanning lase...
Culture and characterization of microglia from the adult murine retina
2014
Purpose. To develop a protocol for isolating and culturing murine adult retinal microglia and to characterize the phenotype and function of the cultured cells. Method. Retinal single-cell suspensions were prepared from adult MF1 mice. Culture conditions including culture medium, growth factors, seeding cell density, and purification of microglia from the mixed cultures were optimised. Cultured retinal microglial cells were phenotyped using the surface markers CD45, CD11b, and F4/80. Their ability to secrete proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation was examined using cytometric bead array (CBA) assay. Results. Higher yield was obtained when retinal single-cell suspension was cultured at the density of 0.75 × 10 6 cells per cm 2 in Dulbecco's modified Eagle medium (DMEM)/F12 + Glutamax supplement with 20% fetal calf serum (FCS) and 20% L929 supernatant. We identified day 10 to be the optimum day of microglial isolation. Over 98% of the cells isolated were positive for CD45, CD11b, and F4/80. After stimulating with LPS they were able to secrete proinflammatory cytokines such as IL-6 and TNF-and express CD86, CD40, and MHC-II. Conclusion. We have developed a simple method for isolating and culturing retinal microglia from adult mice.