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

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 tetracycline antibiotic, minocycline, appears to inhibit proinflammatory 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. 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 DAM. We demonstrate in the Rho-/- mice, IBA1+ and P2RY12+ microglia take on an 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. Overall, we show that minocycline suppresses many DAM markers, in particular those associated with lipid metabolism indicating that suppression of this process is one mechanism by which minocycline protects against inflammation induced photoreceptor cell death.

Automated summary

As resident immune cells in the retina, microglia play crucial roles in maintaining immune regulation and protecting neurons. However, chronic microglia activation is common in degenerative retinal diseases. Minocycline, a semi-synthetic tetracycline antibiotic, has shown to inhibit proinflammatory microglia and protect against photoreceptor cell degeneration. Disease associated microglia (DAM), a subtype of microglia, have been associated with various central nervous system (CNS) diseases. This study investigates the infiltration of microglia towards the outer retina in rhodopsin knockout mice and identifies markers for both homeostatic function and DAM. The administration of minocycline to the mice leads to the suppression of DAM markers associated with lipid metabolism, thus protecting against inflammation-induced photoreceptor cell death.