Upregulation of P2RX7 in<i>Cx3cr1</i>-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration

Hu, Shulong J.; Calippe, Bertrand; Lavalette, Sophie; Roubeix, Christophe; Montassar, Fadoua; Housset, Michael; Levy, Olivier; Delarasse, Cécile; Pâques, Michel; Sahel, José‐Alain; Sennlaub, Florian; Guillonneau, Xavier

doi:10.1523/jneurosci.3955-14.2015

Cited by 85 publications

(101 citation statements)

References 59 publications

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“…Previously published studies show that no difference existed between Het and WT mice regarding surface expression of CX3CR1 [32,37]. Furthermore, other studies have made direct comparisons between WT and KO [38–40]. …”

Section: Discussionmentioning

confidence: 99%

CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes

Beli

Dominguez

et al. 2016

J Mol Med

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In this study, the role of CX3CR1 in the progression of diabetic retinopathy (DR) was investigated. The retinas of wild type (WT), CX3CR1 null (CX3CR1gfp/gfp, KO) and heterozygous (CX3CR1+/gfp, Het) mice were compared in the presence and absence of streptozotocin (STZ) induced diabetes. CX3CR1 deficiency in STZ-KO increased vascular pathology at 4 months of diabetes, as a significant increase in acellular capillaries was observed only in the STZ-KO group. CX3CR1 deficiency and diabetes had similar effects on retinal neurodegeneration measured by an increase in DNA fragmentation. Retinal vascular pathology in STZ-KO mice was associated with increased numbers of monocyte-derived macrophages in the retina. Furthermore, compared to STZ-WT, STZ-KO mice exhibited increased numbers of inflammatory monocytes in the bone marrow and impaired homing of monocytes to the spleen. Induction of retinal IL-10 expression by diabetes was significantly less in KO mice, and when bone marrow-derived macrophages from KO mice were maintained in high glucose they expressed significantly less IL-10 and more TNF-α in response to LPS stimulation. These findings support that CX3CR1 deficiency accelerates the development of vascular pathology in DR through increased recruitment of proinflammatory myeloid cells that demonstrate reduced expression of anti-inflammatory IL-10.

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Section: Discussionmentioning

confidence: 99%

CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes

Beli

Dominguez

et al. 2016

J Mol Med

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“…Two characteristic features of low grade retinal chronic inflammation are complement deposition at Bruch's membrane and an increased number of subretinal microglia/ macrophages (43). Although studies suggest a beneficial effect of these subretinal immune cells in tissue homeostasis (43)(44)(45), detrimental roles of activated microglial cells have been documented in AMD patients (46) and various disease models (47,48). In this study, invasion of microglia into the subretinal space was documented in mice with retinal degeneration caused by Mertk deficiency.…”

Section: Journal Of Biological Chemistry 26943mentioning

confidence: 75%

Receptor MER Tyrosine Kinase Proto-oncogene (MERTK) Is Not Required for Transfer of Bis-retinoids to the Retinal Pigmented Epithelium

Palczewska

Maeda

Golczak

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanAccumulation of bis-retinoids in the retinal pigmented epithelium (RPE) is a hallmark of aging and retinal disorders such as Stargardt disease and age-related macular degeneration. These aberrant fluorescent condensation products, including di-retinoid-pyridinium-ethanolamine (A2E), are thought to be transferred to RPE cells primarily through phagocytosis of the photoreceptor outer segments. However, we observed by twophoton microscopy that mouse retinas incapable of phagocytosis due to a deficiency of the c-Mer proto-oncogene tyrosine kinase (Mertk) nonetheless contained fluorescent retinoid condensation material in their RPE. Primary RPE cells from Mertk ؊/؊ mice also accumulated fluorescent products in vitro.Finally, quantification of A2E demonstrated the acquisition of retinal condensation products in Mertk ؊/؊ mouse RPE prior to retinal degeneration. In these mice, we identified activated microglial cells that likely were recruited to transport A2E-like condensation products to the RPE and dispose of the dying photoreceptor cells. These observations demonstrate a novel transport mechanism between photoreceptor cells and RPE that does not involve canonical Mertk-dependent phagocytosis.Maintaining the health of the vertebrate retina requires a delicate interaction between retinal photoreceptor cells, which collect and transmit visual stimuli, and the adjacent retinal pigmented epithelium (RPE), 4 a cell layer that forms part of the blood-retina barrier (1). Disturbances in this interaction, whether through genetic defects, environmental insults, or trauma can lead to retinal degeneration and ultimate loss of vision (2, 3). The RPE performs many vital functions, including the daily removal of the older distal portions of photoreceptor outer segments (4 -6) and the delivery of both nutrients and the 11-cis-retinal chromophore to rod and cone photoreceptor cells that sustain vision (7). Roughly 10% of each photoreceptor cell outer segment is shed daily throughout an animal's life, distinguishing the RPE as perhaps the most active phagocytic cell layer in the body (5). Although RPE phagocytosis was discovered over 40 years ago (4), the molecular mechanisms underlying this process have not been delineated. However, certain molecular components that support classic phagocytosis have been identified, including the tyrosine receptor kinase Mertk (8, 9). The RPE not only removes toxic photo-oxidation products that accumulate in the retina, but it also recycles usable materials such as proteins, lipids, and small molecules. Retinoid condensation products such as bis-retinoids (di-retinoidpyridinium-ethanolamine (A2E), retinoid dimers, and others) generated in photoreceptors are presumably transported along with photoreceptor membranes to the RPE during phagocytosis. Highly fluorescent A2E accumulation is a pathogenic hallmark of Stargardt disease, the most common juvenile form of human macular degeneration (10). A2E accumulation also is thought to contribute to the pathogenesis of age-related mac...

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“…One signal stimulates pro-IL-1β transcription (via TLR signaling), while the second (best studied via ATP-P2X7 receptor interaction) promotes IL-1β secretion via caspase-1-mediated cleavage of pro-IL-1β (44). In a model of macular degeneration, infiltrating mononuclear cells from CX3CR1-deficient mice were found to upregulate P2X7 expression with an increase in IL-1β secretion causing retinal damage (45). These data collectively suggest that CX3CR1 expression in monocytes and macrophages helps suppress IL-1β production to limit IL-17 production from lung γδ T cells in the context of RSV infection.…”

Section: Discussionmentioning

confidence: 99%

Respiratory syncytial virus infection of newborn CX3CR1-deficent mice induces a pathogenic pulmonary innate immune response

et al. 2017

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Upregulation of P2RX7 inCx3cr1-Deficient Mononuclear Phagocytes Leads to Increased Interleukin-1β Secretion and Photoreceptor Neurodegeneration

Cited by 85 publications

References 59 publications

CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes

CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes

Receptor MER Tyrosine Kinase Proto-oncogene (MERTK) Is Not Required for Transfer of Bis-retinoids to the Retinal Pigmented Epithelium

Respiratory syncytial virus infection of newborn CX3CR1-deficent mice induces a pathogenic pulmonary innate immune response

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