Administered RSPO3 and RSPO3 secreted by endothelial cells promote neurite outgrowth and neuroprotection by suppressing TLR2, TLR4, and TLR9-induced inflammation in microglia and by acting directly on neurons (A). RSPO3 stimulates nuclear translocation of β-catenin, resulting in the downregulation of TLR4 expression and promotion of neurite outgrowth (B).