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Critical Role of Monocyte Recruitment in Optic Nerve Damage Induced by Experimental Optic Neuritis

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Abstract

Neuroinflammatory diseases are characterized by blood-brain barrier disruption (BBB) and leukocyte infiltration. We investigated the involvement of monocyte recruitment in visual pathway damage provoked by primary optic neuritis (ON) induced by a microinjection of bacterial lipopolysaccharide (LPS) into the optic nerve from male Wistar rats. Increased Evans blue extravasation and cellularity were observed at 6 h post-LPS injection. In WT-GFPþ/WT chimeric rat optic nerves, the presence of GFP(+) neutrophils and GFP(+) monocytes, and in wild-type rat optic nerves, an increase in CD11b+CD45low and CD11b+CD45high cell number, were observed at 24 h post-LPS. Gamma-irradiation did not affect the increase in BBB permeability, but significantly lessened the decrease in pupil light reflex (PLR), and retinal ganglion cell (RGC) number induced by LPS. At 6 h post-LPS, an increase in chemokine (C-C motif) ligand 2 (CCL2) immunoreactivity co-localized with neutrophils (but not microglia/macrophages or astrocytes) was observed, while at 24 h post-injection, an increase in Iba-1-immunoreactivity and its co-localization with CCL2 became evident. The co-injection of LPS with bindarit (a CCL2 synthesis inhibitor) lessened the effect of LPS on PLR, and RGC loss. The treatment with etoposide or gadolinium chloride that significantly decreased peripheral monocyte (but not neutrophil or lymphocyte) percentage decreased the effect of LPS on PLR, and RGC number. Moreover, a negative correlation between PRL and monocyte (but not lymphocyte or neutrophil) percentage was observed at 7 days post-LPS. Taken together, these results support that monocytes are key players in the initial events that take place during primary ON.

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Funding

This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica (PICT 1563, PICT 2731), The University of Buenos Aires (20020130100564), and Consejo Nacional de Investigaciones Científicas y Técnicas (PIP 0707), Argentina. The funding organizations have no role in the design or conduct of this research.

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  1. Department of Human Biochemistry, Laboratory of Retinal Neurochemistry and Experimental Ophthalmology School of Medicine/CEFyBO, University of Buenos Aires/CONICET, Buenos Aires, Argentina

    Marcos L. Aranda, María F. González Fleitas, Florencia Altschuler, Hernán H. Dieguez, María I. Keller Sarmiento, Mónica S. Chianelli, Pablo H. Sande, Damián Dorfman & Ruth E. Rosenstein

  2. Laboratory of Immunomodulators and ORGAN REGENERATION, School of Medicine/CEFyBO, University of Buenos Aires/CONICET, Buenos Aires, Argentina

    Diego Guerrieri

  3. Department of Biological Chemistry and Institute of Chemistry and Biological Physicochemistry, School of Pharmacy and Biochemistry, University of Buenos Aires/CONICET, Buenos Aires, Argentina

    Gonzalo Piñero

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  1. Marcos L. Aranda
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All animal procedures were in strict accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. The ethic committee of the School of Medicine, University of Buenos Aires (Institutional Committee for the Care and Use of Laboratory Animals, (CICUAL)) approved this study, and all efforts were made to minimize animal suffering.

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Fig. 9

Representative photomicrographs of consensual PLR (left panel) and Brn3a-immunostaining in flat-mounted retinas (right panel) from vehicle, etoposide- or gadolinium chloride (GdCl3)-treated animals, whose optic nerves were injected with vehicle or LPS (PNG 2605 kb)

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Aranda, M.L., Guerrieri, D., Piñero, G. et al. Critical Role of Monocyte Recruitment in Optic Nerve Damage Induced by Experimental Optic Neuritis. Mol Neurobiol 56, 7458–7472 (2019). https://doi.org/10.1007/s12035-019-1608-0

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