Docosahexaenoic acid attenuates microglial activation and delays early retinal degeneration.
Microgliosis is a common phenomenon in neurodegenerative disorders including retinal dystrophies. We performed a detailed characterization of activated microglia in the retinoschisin (Rs1h)-deficient (Rs1h(-/Y)) mouse model of inherited retinal degeneration. To visualize and isolate microglia, we crossed Rs1h(-/Y) animals with transgenic MacGreen mice, which express green fluorescent protein under the control of the macrophage-specific csf1r promoter. Activated microglia were detected in retinal sections and whole-mounts of early postnatal MacGreen/Rs1h(-/Y) mice before the onset of overt neuronal cell death. These activated microglia contained prominent lipid droplets and analysis of the retinal lipid composition showed decreased docosahexaenoic acid (DHA) levels in Rs1h(-/Y) retinas. To establish a link between microglia activation, reduced DHA levels, and neurodegeneration, a dietary intervention study was performed. Female Rs1h(-/-) mice and their Rs1h(-/Y) litter were either subjected to a diet enriched with DHA, or a control chow lacking DHA. Supplementation with DHA enhanced photoreceptor survival and converted activated microglia to a quiescent phenotype. Furthermore, DHA, but not docosapentaenoic acid or adrenic acid reduced pro-inflammatory gene expression, migration, and lipid accumulation of cultured BV-2 microglia. We conclude that retinal DHA levels control the activity of microglia and thereby may affect the progression and extent of retinal degeneration.
Ebert
Stefanie
S
Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
Weigelt
Karin
K
Walczak
Yana
Y
Drobnik
Wolfgang
W
Mauerer
Richard
R
Hume
David A
DA
Weber
Bernhard H F
BH
Langmann
Thomas
T
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015815:Cell Adhesion Molecules / Q000172:deficiency; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005136:Eye Proteins; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D020287:In Situ Nick-End Labeling / Q000379:methods; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010743:Phospholipids / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D015815:Cell Adhesion Molecules; D005136:Eye Proteins; D005227:Fatty Acids; D008070:Lipopolysaccharides; D010743:Phospholipids; C491843:RS1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D004281:Docosahexaenoic Acids