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

Abstract

Background: As the resident immune cells in the retina, microglia play important homeostatic roles in retinal immune regulation and neuroprotection. However, chronic microglia activation is a common hallmark of many degenerative retinal diseases. The semi-synthetic broad spectrum tetracycline antibiotic, minocycline appears to inhibit pro-inflammatory microglia which coincides with protection against photoreceptor cell degeneration. A sub-type of microglia termed disease associated microglia ( DAM) have recently been associated with a wide range of central nervous system (CNS) diseases.Methods: In this study we examine the kinetics of microglia infiltration towards the outer retina of rhodopsin knockout mice ( rho -/- ) by immunofluorescence, and undertake transcriptional and spatial localization analysis of markers for evidence of both homeostatic function and appearance of DAMs. Results: We demonstrate in the Rho-/- mice that Iba1 + and P2RY12 + microglia take on activated morphology early in disease, prior to notable photoreceptor loss and are capable of infiltrating the subretinal space. Expression of lipid processing enzyme and DAM-marker lipoprotein lipase (LPL) is primarily observed only after microglia have traversed the ONL. Administration of minocycline to Rho-/- mice induced loss of phagocytic/DAM microglia in the outer retina in vivo coinciding with photoreceptor survival and amelioration of retinal degeneration. Conclusion: Our study identifies microglial lipid processing enzyme and DAM-marker lipoprotein lipase (LPL) as a direct target of minocycline and indicates that suppression of lipid metabolism is one mechanism by which minocycline protects against inflammation induced photoreceptor cell death.