Ccr2 suppression by minocycline in Cx3cr1/Ccr2-visualized inherited retinal degeneration

Abstract

Retinal inflammation accelerates photoreceptor cell death (PCD) caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has previously been reported to show PCD rescue effect in retinal degeneration. The purpose of this study was to assess the effect of minocycline on Cx3cr1 and Ccr2 expression in retinal degeneration. Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled observation of Cx3cr1- and Ccr2-expression pattern in inherited retinal degeneration, were used to test the effect of minocycline. Minocycline was systemically administered to Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice. For observing the effect of minocycline on Cx3cr1 and Ccr2 expression, administration was started on 4-week-old mice and continued for 2 weeks. To assess the PCD rescue effect, minocycline was administered to 6-week-old mice for 2 weeks. The expression pattern of Cx3cr1-GFP and Ccr2-RFP were observed on retinal and retinal pigment epithelium (RPE) flat-mounts. The severity of retinal degeneration was assessed on retinal sections. Minocycline administration suppressed Ccr2 expression in Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice as observed in retinal and RPE flat-mounts. On the contrary, Cx3cr1 expression was not affected by minocycline administration. Retinal degeneration is ameliorated in minocycline administered Mertk-/-Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusions, Minocycline suppression of Ccr2 expression correlates to amelioration of retinal degeneration.

Minocycline suppresses disease-associated microglia (DAM) in a model of photoreceptor cell degeneration

“…Overall, our data supports other studies demonstrating the therapeutic efficacy of minocycline in retinal degeneration; minocycline treatment has previously been shown to preserve the morphology and function of photoreceptors in the rd10 mouse model (Peng, Xiao et al 2014), in a light-damage-induced RD model (Scholz, Sobotka et al 2015) and more recently, in the Mertk -/mouse model of RD (Terauchi, Kohno et al 2021). It is important to consider, however, that triggering early DAM activation may be useful to induce a microglia response in diseases where a strong phagocytic activity might be beneficial.…”

“…Minocycline, a broad-spectrum tetracycline antibiotic, has previously been reported to ameliorate photoreceptor cell death in numerous mouse models of retinal degeneration (Zhang, Lei et al 2004, Kohno, Chen et al 2013, Peng, Xiao et al 2014, Scholz, Sobotka et al 2015, Dannhausen, Möhle et al 2018, Terauchi, Kohno et al 2021) and is a known inhibitor of microglial activation.…”

“…Interestingly expression of lipid processing enzyme and DAM-marker lipoprotein lipase (LPL) is primarily observed only after microglia have traversed the ONL. Recent literature indicates that the semi-synthetic broad spectrum tetracycline antibiotic, minocycline, may have potential to counter-regulate pro-inflammatory microglia and protect photoreceptor cell degeneration (Peng, Xiao et al 2014, Scholz, Sobotka et al 2015, Terauchi, Kohno et al 2021.…”