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Journal of Neuroinflammation

, 12:188

First Online: 12 October 2015Received: 17 April 2015Accepted: 02 October 2015

Abstract

BackgroundThough accumulating evidence suggests that microglia, resident macrophages in the retina, and bone marrow-derived macrophages can cause retinal inflammation which accelerates photoreceptor cell death, the details of how these cells are activated during retinal degeneration RD remain uncertain. Therefore, it is important to clarify which cells play a dominant role in fueling retinal inflammation. However, distinguishing between microglia and macrophages is difficult using conventional techniques such as cell markers e.g., Iba-1. Recently, two mouse models for visualizing chemokine receptors were established, Cx3cr1 and Ccr2 mice. As Cx3cr1 is expressed in microglia and Ccr2 is reportedly expressed in activated macrophages, these mice have the potential to distinguish microglia and macrophages, yielding novel information about the activation of these inflammatory cells and their individual roles in retinal inflammation.

MethodsIn this study, c-mer proto-oncogene tyrosine kinase Mertk mice, which show photoreceptor cell death due to defective retinal pigment epithelium phagocytosis, were employed as an animal model of RD. MertkCx3cr1Ccr2 mice were established by breeding Mertk, Cx3cr1, and Ccr2 mice. The retinal morphology and pattern of inflammatory cell activation and invasion of MertkCx3cr1Ccr2 mice were evaluated using retina and retinal pigment epithelium RPE flat mounts, retinal sections, and flow cytometry.

ResultsFour-week-old MertkCx3cr1Ccr2 mice showed Cx3cr1-GFP-positive microglia in the inner retina. Cx3cr1-GFP and Ccr2-RFP dual positive activated microglia were observed in the outer retina and subretinal space of 6- and 8-week-old animals. Ccr2-RFP single positive bone marrow-derived macrophages were observed to migrate into the retina of MertkCx3cr1Ccr2 mice. These invading cells were still observed in the subretinal space in 18-week-old animals.

ConclusionsCx3cr1-GFP-positive microglia and Ccr2-RFP-positive macrophages were distinguishable in the retinas of MertkCx3cr1Ccr2 mice. In addition, Ccr2 expression in Cx3cr1 positive microglia is a feature of microglial activation in RD. MertkCx3cr1Ccr2 mice enabled observation of microglial activation over time during RD and may be useful for developing inflammation-targeted treatment strategies for RD in the future.

KeywordsMicroglia Chemokine Photoreceptor Cell migration Inflammation AbbreviationsCCLC-C motif ligand

CNScentral nervous system

EAEexperimental autoimmune encephalomyelitis

IHCimmunohistochemistry

ISinner segments

Mertkc-mer proto-oncogene tyrosine kinase

ONLouter nuclear layer

OSouter segments

PCDphotoreceptor cell death

RCSRoyal College of Surgeons

RDretinal degeneration

WBCwhite blood cells

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Autor: Hideo Kohno - Hideto Koso - Kiichiro Okano - Thomas R. Sundermeier - Saburo Saito - Sumiko Watanabe - Hiroshi Tsuneoka - T

Fuente: https://link.springer.com/







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