Sfrp2 in Microglia Inhibited S100a8-Mediated Neuroinflammation and Protected Neural Damage Following Retinal Ischemia-Reperfusion

Purpose: The purpose of this study was to explore retinal Sfrp2 expression, functional roles, and underlying mechanism in retinal ischemia reperfusion (I/R). Methods: We established an I/R mouse model in vivo and a lipopolysaccharide-stimulated BV2 model in vitro. Immunohistochemistry and Western blotting (WB) assessed Sfrp2 expression in human retinal tissue, and WB further evaluated its expression in I/R model. Immunofluorescence staining was used to define its localization. Sfrp2 expression was ablated by Cre-lox mediated conditional deletion in mouse retinal microglia and by siRNA-mediated knockdown in BV2 cells. Hematoxylin and eosin staining, immunofluorescence, and TUNEL staining were applied for evaluating retinal structure, survival of inner retinal neurons, and cell apoptosis, respectively. Retinal function was evaluated by electroretinography. RNA-sequencing, WB, and immunoprecipitation were used to elucidate the underlying mechanisms. Results: Sfrp2 was highly expressed in the retina subjected to I/R injury. Sfrp2 was shown to localize in microglia in an I/R model. Correspondingly, microglial Sfrp2 deficiency exacerbated the retinal structural damage, inner retinal neuronal degeneration, visual dysfunction, and microglia-mediated inflammation in the I/R model. Mechanistically, Sfrp2 deficiency activated TRAF6-TAK1-NF-κB signaling cascade by promoting the TRAF6-TAK1 complex formation, subsequently increasing the expression of downstream inflammatory mediator S100a8. Importantly, S100a8 inhibitor could partially mitigate the retinal injury induced by microglial Sfrp2 deficiency following I/R. Conclusions: Sfrp2 in microglia inhibits TRAF6-TAK1-NF-κB signaling pathway and downstream inflammatory mediator S100a8 thereby attenuating neuroinflammation and protecting the retina in I/R. Sfrp2 may represent a protective strategy for neuronal degeneration in ischemic retinopathy.