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      CCR2 + monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice

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          Abstract

          Atrophic age-related macular degeneration (AMD) is associated with the subretinal accumulation of mononuclear phagocytes (MPs). Their role in promoting or inhibiting retinal degeneration is unknown. We here show that atrophic AMD is associated with increased intraocular CCL2 levels and subretinal CCR2 + inflammatory monocyte infiltration in patients. Using age- and light-induced subretinal inflammation and photoreceptor degeneration in Cx3cr1 knockout mice, we show that subretinal Cx3cr1 deficient MPs overexpress CCL2 and that both the genetic deletion of CCL2 or CCR2 and the pharmacological inhibition of CCR2 prevent inflammatory monocyte recruitment, MP accumulation and photoreceptor degeneration in vivo. Our study shows that contrary to CCR2 and CCL2, CX3CR1 is constitutively expressed in the retina where it represses the expression of CCL2 and the recruitment of neurotoxic inflammatory CCR2 + monocytes. CCL2/CCR2 inhibition might represent a powerful tool for controlling inflammation and neurodegeneration in AMD.

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          Development of monocytes, macrophages, and dendritic cells.

          Frederic Geissmann, Markus Manz, Steffen Jung … (2010)
          Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
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            Control of microglial neurotoxicity by the fractalkine receptor.

            Astrid E. Cardona, Erik P Pioro, Margaret E Sasse … (2006)
            Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.
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              The Rd8 mutation of the Crb1 gene is present in vendor lines of C57BL/6N mice and embryonic stem cells, and confounds ocular induced mutant phenotypes.

              Mary Mattapallil, Eric F Wawrousek, Chi-Chao Chan … (2012)
              We noted an unexpected inheritance pattern of lesions in several strains of gene-manipulated mice with ocular phenotypes. The lesions, which appeared at various stages of backcross to C57BL/6, bore resemblance to the rd8 retinal degeneration phenotype. We set out to examine the prevalence of this mutation in induced mutant mouse lines, vendor C57BL/6 mice and in widely used embryonic stem cells. Ocular lesions were evaluated by fundus examination and histopathology. Detection of the rd8 mutation at the genetic level was performed by PCR with appropriate primers. Data were confirmed by DNA sequencing in selected cases. Analysis of several induced mutant mouse lines with ocular disease phenotypes revealed that the disease was associated 100% with the presence of the rd8 mutation in the Crb1 gene rather than with the gene of interest. DNA analysis of C57BL/6 mice from common commercial vendors demonstrated the presence of the rd8 mutation in homozygous form in all C57BL/6N substrains, but not in the C57BL/6J substrain. A series of commercially available embryonic stem cells of C57BL/6N origin and C57BL/6N mouse lines used to generate ES cells also contained the rd8 mutation. Affected mice displayed ocular lesions typical of rd8, which were detectable by funduscopy and histopathology as early as 6 weeks of age. These findings identify the presence of the rd8 mutation in the C57BL/6N mouse substrain used widely to produce transgenic and knockout mice. The results have grave implications for the vision research community who develop mouse lines to study eye disease, as presence of rd8 can produce significant disease phenotypes unrelated to the gene or genes of interest. It is suggested that researchers screen for rd8 if their mouse lines were generated on the C57BL/6N background, bear resemblance to the rd8 phenotype, or are of indeterminate origin.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EMBO Mol Med
                Journal ID (iso-abbrev): EMBO Mol Med
                Journal ID (publisher-id): emmm
                Title: EMBO Molecular Medicine
                Publisher: Blackwell Publishing Ltd
                ISSN (Print): 1757-4676
                ISSN (Electronic): 1757-4684
                Publication date (Print): November 2013
                Publication date (Electronic): 21 October 2013
                Volume: 5
                Issue: 11
                Pages: 1775-1793
                Affiliations
                [1 ]Inserm, U 968 Paris, France
                [2 ]UPMC Univ Paris 06, UMR_S 968, Institut de la Vision Paris, France
                [3 ]Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503 Paris, France
                [4 ]Hôtel Dieu, Service d'Ophtalmologie, Centre de Recherche Ophtalmologique Paris, France
                [5 ]Inserm UMR_S 945, Laboratoire Immunité et Infection Paris, France
                [6 ]Université Pierre et Marie Curie-Paris6, UPMC Univ Paris 06, UMR_S 945 Paris, France
                [7 ]Gladstone Institute of Cardiovascular Disease, San Francisco CA, USA
                [8 ]Cardiovascular Research Institute, Department of Medicine, University of California San Francisco San Francisco, CA, USA
                [9 ]Department of Molecular Cell Biology, Free University Medical Center Amsterdam, The Netherlands
                [10 ]Inserm, UMR_S 872, Centre de Recherche des Cordeliers Paris, France
                [11 ]Université Paris Descartes, UMR_S 872, Centre de Recherche des Cordeliers Paris, France
                [12 ]Université Pierre et Marie Curie-Paris6, UPMC Univ Paris 06, UMR_S 872 Paris, France
                [13 ]AP-HP, Groupe Hospitalier Pitié-Salpétrière, Service d'Immunologie Paris, France
                Author notes
                * Corresponding author: Tel: +33 1 53 46 26 93; Fax: +33 1 53 46 26 00; E-mail: florian.sennlaub@ 123456inserm.fr
                ** Corresponding author: Tel: +33 1 40 77 98 92; Fax: +33 1 40 77 97 34; E-mail: christophe.combadiere@ 123456upmc.fr
                [†]

                These authors contributed equally to this work.

                Article
                DOI: 10.1002/emmm.201302692
                PMC ID: 3840491
                PubMed ID: 24142887
                SO-VID: 1fbbc60b-3e9f-44f6-8289-a802caca7d28
                Copyright © © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO
                License:

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                Date received : 28 February 2013
                Date revision received : 28 August 2013
                Date accepted : 30 August 2013
                Categories
                Subject: Research Articles

                ScienceOpen disciplines: Molecular medicine
                Keywords: monocyte,chemokines,neuroinflammation,age-related macular disease,neurodegeneration
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: monocyte, chemokines, neuroinflammation, age-related macular disease, neurodegeneration

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