17β-Estradiol attenuates the influence of chronic activated microglia on SH-SY5Y cell proliferation via canonical WNT signaling pathway

Abstract

The decline in circulating estrogen following menopause or aging is likely to initiate chronic inflammatory disorders, leading to neurodegenerative disease. Though, WNT1 paracrine molecules are crucial in embryonic neuroblastoma cell proliferation, very less is known about its role in adult brain that is associated with estrogen as preventive therapeutic strategy. The present study evidenced for the first time that 17β-estradiol (E2), a potent form of estrogen, could compensate the chronic neuroinflammation-associated loss of neurons by upregulating canonical WNT signaling pathway. Lipopolysaccharide was used to induce inflammatory responses in microglial cell line. The increased secretion of IL-6 cytokine was confirmed as a marker of chronic microglial activation. LPS-conditioned microglial media significantly reduced the viable cells and proliferative markers, BrdU and CyclinD1 in SH-SY5Y. It also decreased the expression of canonical WNT signaling components; WNT1 and β-catenin, which were significantly rescued with pre- and co-treatment of 10 nM E2. Furthermore, estrogen antagonist ICI 182,780 abolished the E2-mediated recovery in WNT1 expression. Whereas, canonical WNT receptor antagonist, Dkk1 was able to inhibit E2-mediated recovery in the expression of downstream component, β-catenin. It suggests a promising role of canonical WNT signaling pathway in estrogen mediated prevention of neuronal cell loss under chronic neuroinflammatory condition.