Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa.

Ryo Terauchi,Sumiko Watanabe,Tadashi Nakano,Hideo Kohno,Saburo Saito,Akira Watanabe,Alfred S Lewin

doi:10.1371/journal.pone.0239108

Ryo Terauchi, Sumiko Watanabe + Show 5 more

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https://doi.org/10.1371/journal.pone.0239108

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Abstract

Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)-/-Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.

Highlights

Inflammation in the central nervous system, as well as the retina, is considered a complicating factor in degenerative diseases [1,2,3,4,5]
We found that minocycline administration to mer proto-oncogene tyrosine kinase (Mertk)−/−Cx3cr1GFP/+Ccr2RFP/+ mice ameliorated photoreceptor cell death (PCD) and reduced the number of CCR2-red fluorescent protein (RFP)-positive cells in the outer retina and subretinal space
Representative CX3CR1-green fluorescent protein (GFP) single-positive cells observed in retinal flat-mounts of 4-week-old Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice and CX3CR1/CCR2 double-positive cells observed in retinal pigment epithelium (RPE) flat-mounts of 6-week-old Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice are presented in Fig 1A and 1B

Summary

Introduction

Inflammation in the central nervous system, as well as the retina, is considered a complicating factor in degenerative diseases [1,2,3,4,5]. Retinal inflammation is considered to accelerate photoreceptor cell death (PCD) in retinal degeneration (RD), including age-related macular degeneration and retinitis pigmentosa [6].

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