Lipoxin A4 delays the progression of retinal degeneration via the inhibition of microglial overactivation

Background: Retinal degeneration (RD) is characterized by progressive photoreceptor degeneration, and emerging evidence has demonstrated that activated microglia-mediated inflammation exacerbates the progression of RD. Lipoxin A4 (LXA4) is an endogenous neuroprotective lipid mediator, but the potential therapeutic roles of LXA4 in RD have not been evaluated. Methods: Electroretinogram (ERG) recordings and behavioral tests were used to analyze whether the intravitreal injection (IVI) of LXA4 restored visual function in RD1 mice. Immunostaining, qPCR, western blotting and mouse cytokine arrays using an ex-vivo retinal explant model were successively performed to explore the mechanisms underlying the effects of LXA4. Results: The key rate-limiting enzyme in LXA4 biosynthesis and the LXA4 receptor were substantially downregulated in end-stage RD1 retinas. LXA4 maintained visual function in RD1 mice from postnatal days 15-21 (PN15 to PN21). Moreover, LXA4 modulated microglial activities, significantly inhibited proinflammatory gene expression, and thereby attenuated photoreceptor apoptosis. Conclusions: LXA4 delayed the progression of RD, and thus, the use of LXA4 might be a novel approach for ameliorating dysfunction in neurodegenerative disorders. (C) 2019 Elsevier Inc. All rights reserved.