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      Relationship between Uveitis and the Differential Reactivity of Retinal Microglia

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          Abstract

          Uveitis, a complicated group of ocular inflammatory diseases, can be affected by massive pathogenic contributors such as infection, autoimmunity, and genetics. Although it is well known that many pathological changes, including disorders of the immune system and disruption of the blood-retinal barrier, count much in the onset and progression of uveitis, there is a paucity of safe and effective treatments, which has exceedingly hindered the appropriate treatment of uveitis. As innate immune cells in the retina, microglia occupy a salient position in retinal homeostasis. Many studies have reported the activation of microglia in uveitis and the mitigation of uveitis by interfering with microglial reactivity, which strongly implicates microglia as a therapeutic target. However, it has been increasingly recognized that microglia are a nonhomogeneous population under different physiological and pathological conditions, which makes it essential to thoroughly have knowledge of their specific characteristics. The paper outlines the various properties of activated microglia in uveitis, summarizes the connections between their polarization patterns and the manifestations of uveitis, and ultimately is intended to enhance the understanding of microglial versatility and expedite the exploration of promising strategies for visual protection.

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          Most cited references58

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          Origin, fate and dynamics of macrophages at central nervous system interfaces

          Perivascular, subdural meningeal and choroid plexus macrophages are non-parenchymal macrophages that mediate immune responses at brain boundaries. Although the origin of parenchymal microglia has recently been elucidated, much less is known about the precursors, the underlying transcriptional program and the dynamics of the other macrophages in the central nervous system (CNS). It was assumed that they have a high turnover from blood-borne monocytes. However, using parabiosis and fate-mapping approaches in mice, we found that CNS macrophages arose from hematopoietic precursors during embryonic development and established stable populations, with the notable exception of choroid plexus macrophages, which had dual origins and a shorter life span. The generation of CNS macrophages relied on the transcription factor PU.1, whereas the MYB, BATF3 and NR4A1 transcription factors were not required.
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            Microglial Function Is Distinct in Different Anatomical Locations during Retinal Homeostasis and Degeneration

            Microglia from different nervous system regions are molecularly and anatomically distinct, but whether they also have different functions is unknown. We combined lineage tracing, single-cell transcriptomics, and electrophysiology of the mouse retina and showed that adult retinal microglia shared a common developmental lineage and were long-lived but resided in two distinct niches. Microglia in these niches differed in their interleukin-34 dependency and functional contribution to visual-information processing. During certain retinal-degeneration models, microglia from both pools relocated to the subretinal space, an inducible disease-associated niche that was poorly accessible to monocyte-derived cells. This microglial transition involved transcriptional reprogramming of microglia, characterized by reduced expression of homeostatic checkpoint genes and upregulation of injury-responsive genes. This transition was associated with protection of the retinal pigmented epithelium from damage caused by disease. Together, our data demonstrate that microglial function varies by retinal niche, thereby shedding light on the significance of microglia heterogeneity.
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              Metabolic Reprograming of Microglia in the Regulation of the Innate Inflammatory Response

              Microglia sustain normal brain functions continuously monitoring cerebral parenchyma to detect neuronal activities and alteration of homeostatic processes. The metabolic pathways involved in microglia activity adapt at and contribute to cell phenotypes. While the mitochondrial oxidative phosphorylation is highly efficient in ATP production, glycolysis enables microglia with a faster rate of ATP production, with the generation of intermediates for cell growth and cytokine production. In macrophages, pro-inflammatory stimuli induce a metabolic switch from oxidative phosphorylation to glycolysis, a phenomenon similar to the Warburg effect well characterized in tumor cells. Modification of metabolic functions allows macrophages to properly respond to a changing environment and many evidence suggest that, similarly to macrophages, microglial cells are capable of a plastic use of energy substrates. Neuroinflammation is a common condition in many neurodegenerative diseases and the metabolic reprograming of microglia has been reported in neurodegeneration. Here we review the existing data on microglia metabolism and the connections with neuroinflammatory diseases, highlighting how metabolic changes contribute to module the homeostatic functions of microglia.
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                Author and article information

                Journal
                Ophthalmic Res
                Ophthalmic Res
                ORE
                ORE
                Ophthalmic Research
                S. Karger AG (Basel, Switzerland )
                0030-3747
                1423-0259
                4 September 2023
                Jan-Dec 2023
                : 66
                : 1
                : 1206-1212
                Affiliations
                [1]Department of Ophthalmology, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Henan Province Eye Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
                Author notes
                Correspondence to: Liping Du, dulplab@ 123456live.cn
                Article
                531156
                10.1159/000531156
                10614524
                37666222
                4ea473f4-f1d9-41b4-8a2a-830af05f7a19
                © 2023 The Author(s).Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) ( http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

                History
                : 23 January 2023
                : 9 May 2023
                : 2023
                Page count
                Figures: 1, References: 58, Pages: 7
                Funding
                This work was supported by the National Natural Science Foundation of China (Grant Nos. 81970792 and 82171040) and the Medical Science and Technology Project of the Health Commission of Henan Province (Grant No. YXKC2020026).
                Categories
                Review Article

                uveitis,microglia,inflammatory/immune response,blood-retinal barrier,heterogeneity

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